IL-1 β binding antibodies for the treatment of cancer
阅读说明：本技术 用于治疗癌症的IL-1β结合抗体 (IL-1 β binding antibodies for the treatment of cancer ) 是由 M·利格罗斯-萨伊兰 P·马特查巴 T·索伦 P·里德凯尔 P·莉比 P·奥特韦尔 Y· 于 2018-06-22 设计创作，主要内容包括：本公开涉及IL-1β结合抗体或其功能片段、尤其是卡那吉努单抗或其功能片段或格沃吉珠单抗或其功能片段、以及生物标志物在治疗和/或预防具有至少部分炎症基础的癌症中的用途。(The present disclosure relates to the use of IL-1 β binding antibodies or functional fragments thereof, in particular canargiunumab or functional fragments thereof or gavagizumab or functional fragments thereof, and biomarkers for the treatment and/or prevention of cancer with at least a partial basis for inflammation.)
1. An IL-1 β binding antibody or a functional fragment thereof for use in the treatment and/or prevention of a cancer having at least a partial basis for inflammation in a patient in need thereof.
2. An IL-1 β binding antibody or functional fragment thereof for use in treating a cancer having at least a partial basis for inflammation in a patient in need thereof, wherein the IL-1 β binding antibody or functional fragment is administered at a dose of about 30mg to about 450mg per treatment.
3. The use of claim 1 or 2, wherein the cancer having at least a partial basis for inflammation is selected from the list consisting of: lung cancer, particularly non-small cell lung cancer (NSCLC); colorectal cancer (CRC); melanoma; stomach cancer (including esophageal cancer); renal Cell Carcinoma (RCC); breast cancer; prostate cancer; head and neck cancer; bladder cancer; hepatocellular carcinoma (HCC); ovarian cancer; cervical cancer; endometrial cancer; pancreatic cancer; neuroendocrine cancer; multiple myeloma; acute Myeloid Leukemia (AML) and biliary tract cancer.
4. The use of claim 1 or 2, wherein the cancer having at least a partial basis for inflammation is selected from the list consisting of: lung cancer, particularly non-small cell lung cancer (NSCLC); colorectal cancer (CRC); melanoma; stomach cancer (including esophageal cancer); renal Cell Carcinoma (RCC); breast cancer; hepatocellular carcinoma (HCC); prostate cancer; bladder cancer; acute Myeloid Leukemia (AML); multiple myeloma and pancreatic cancer.
5. The use according to claim 1 or 2, wherein the cancer having at least a partial basis of inflammation is colorectal cancer (CRC).
6. The use of claim 1 or 2, wherein the cancer having at least a partial basis for inflammation is Renal Cell Carcinoma (RCC).
7. The use of claim 1 or 2, wherein the cancer having at least a partial basis for inflammation is breast cancer.
8. Use according to claim 1 or 2, wherein the cancer having at least a partial basis for inflammation is lung cancer, preferably non-small cell lung cancer (NSCLC).
9. The use of any one of the preceding claims, wherein the patient has equal to or greater than about 2mg/L of high sensitivity C-reactive protein (hsCRP) prior to the first administration of the IL-1 β binding antibody or functional fragment thereof.
10. The use of any one of the preceding claims, wherein the patient has equal to or greater than 4mg/L or equal to or greater than 10mg/L of high sensitivity C-reactive protein (hsCRP) prior to the first administration of the IL-1 β binding antibody or functional fragment thereof.
11. The use of any one of the preceding claims, wherein the patient has reduced the level of high sensitivity C-reactive protein (hsCRP) assessed at least about 3 months after the first administration of IL-1 β binding antibody or functional fragment thereof to less than about 5mg/L, 3.5mg/L, 2.3mg/L, preferably to less than about 2mg/L, preferably to less than about 1.8 mg/L.
12. The use of any one of the preceding claims, wherein the patient has at least a 20% reduction in the level of high sensitivity C-reactive protein (hsCRP) assessed at least about 3 months after the first administration of IL-1 β -binding antibody or functional fragment thereof, as compared to baseline.
13. The use of any one of the preceding claims, wherein the patient has at least a 20% reduction in interleukin-6 (IL-6) levels assessed at least about 3 months after the first administration of an IL-1 β binding antibody or functional fragment thereof, as compared to baseline.
14. The use of any one of the preceding claims, wherein the use comprises administering the IL-1 β binding antibody or functional fragment thereof every two weeks, every three weeks, or every four weeks (monthly).
15. The use of any one of the preceding claims, wherein the IL-1 β binding antibody is canajirimumab.
16. The use of any one of the preceding claims, comprising administering to the patient about 200mg to about 450mg of canargiunumab per treatment.
17. The use of claim 16, comprising administering to the patient about 200mg of canajirimumab per treatment.
18. The use of any one of claims 15-17, wherein canargiunumab is administered every three weeks.
19. The use of any one of claims 15-17, wherein canargiunumab is administered every four weeks (monthly).
20. The use of any one of claims 15-19, wherein canargizumab is administered subcutaneously.
21. The use of any one of claims 15-19, wherein canargizumab is administered intravenously.
22. Canargiunumab for use in treating a cancer having at least a partial basis of inflammation, preferably lung cancer, in a patient in need thereof, wherein the use comprises subcutaneously administering a dose of 200mg canargiunumab every three weeks.
23. The use of any one of claims 1-14, wherein the IL-1 β binding antibody is gavoglizumab (XOMA-052).
24. The use of claim 23, wherein the use comprises administering 30mg to 90mg of gemfibrolizumab to the patient per treatment.
25. The use of claim 23, comprising administering to the patient from about 90mg to about 120mg of gemfibrozumab per treatment.
26. The use of any one of claims 23-25, wherein gavoglizumab is administered every three weeks.
27. The use of any one of claims 23-25, wherein gavoglizumab is administered every four weeks (monthly).
28. The use of any one of claims 23-27, wherein gavoglizumab is administered subcutaneously.
29. The use of any one of claims 23-27, wherein gemfibrozumab is administered intravenously.
30. Gavoglizumab for use in treating a cancer with at least a partial basis for inflammation in a patient in need thereof, wherein the use comprises intravenously administering a dose of 30mg to 120mg gavoglizumab every four weeks (monthly).
31. The use of claim 30, wherein the cancer having at least a partial basis for inflammation is selected from the list consisting of: lung cancer, particularly non-small cell lung cancer (NSCLC); colorectal cancer (CRC); melanoma; stomach cancer (including esophageal cancer); renal Cell Carcinoma (RCC); breast cancer; hepatocellular carcinoma (HCC); prostate cancer; bladder cancer; acute Myeloid Leukemia (AML); multiple myeloma and pancreatic cancer.
32. The use of any one of the preceding claims, wherein the IL-1 β binding antibody or functional fragment thereof is administered in combination with one or more therapeutic agents, e.g., a chemotherapeutic agent, wherein preferably the IL-1 β binding antibody or functional fragment thereof is canargizumab or gavagizumab.
33. The use of claim 32, wherein the one or more therapeutic agents, such as a chemotherapeutic agent, is a standard of care agent for the cancer.
34. Use according to any one of claims 32 to 33, wherein the one or more therapeutic agents, for example a chemotherapeutic agent, is a standard of care agent for lung cancer, in particular NSCLC.
35. The use of any one of claims 32 to 34, wherein the one or more therapeutic agents are selected from platinum-based chemotherapy, platinum-based duplex chemotherapy (PT-DC), tyrosine kinase inhibitors, or checkpoint inhibitors.
36. The use according to any one of claims 32 to 35, wherein the one or more therapeutic agents, e.g. chemotherapeutic agents, is a PD-1 inhibitor or a PD-L1 inhibitor, preferably selected from the group consisting of: nivolumab, lanolingzumab, alemtuzumab, dulvolumab, avizumab and sibatuzumab (PDR-001).
37. The use according to any one of the preceding claims, wherein said IL-1 β binding antibody or functional fragment thereof is used alone or preferably in combination to prevent the recurrence or relapse of a cancer having at least a partial basis for inflammation in a subject following surgical removal of said cancer.
38. The use of claim 37, wherein the cancer with a partial basis for inflammation is lung cancer.
39. Use according to any one of the preceding claims, wherein the IL-1 β binding antibody or functional fragment thereof, alone or preferably in combination, is used as a first, second or third line treatment of lung cancer, in particular non-small cell lung cancer (NSCLC).
40. An IL-1 β binding antibody or functional fragment thereof for use in preventing lung cancer in a patient, wherein the patient has a level of high sensitivity C-reactive protein (hsCRP) equal to or greater than 2mg/L, or equal to or greater than 4 mg/L.
41. The use of claim 40, wherein the IL-1 β binding antibody or functional fragment thereof is Kanagracelizumab or functional fragment thereof or Gevojizumab or functional fragment thereof.
42. The use of any one of the preceding claims, wherein gemfibrozumab or a functional fragment thereof is administered in combination with one or more therapeutic agents, e.g., a chemotherapeutic agent.
43. The use of claim 32 or 42, wherein the one or more therapeutic agents, e.g., chemotherapeutic agents, is a standard of care agent for colorectal cancer (CRC).
44. The use of claim 42 or 43, wherein the one or more therapeutic agents, e.g. chemotherapeutic agents, are general cytotoxic agents, wherein preferably the general cytotoxic agents are selected from the list consisting of: FOLFOX, FOLFIRI, capecitabine, 5-fluorouracil, irinotecan and oxaliplatin.
45. The use of any one of claims 42 to 44, wherein the one or more therapeutic agents, e.g. chemotherapeutic agents, is a VEGF inhibitor, wherein preferably the VEGF inhibitor is selected from the list consisting of: bevacizumab, ramucirumab and aflibercept.
46. The use of any one of claims 42 to 45, wherein Gevoglizumab or the functional fragment thereof is administered in combination with FOLFIRI plus bevacizumab or FOLFOX plus bevacizumab.
47. The use of any one of claims 42 to 46, wherein the one or more therapeutic agents, such as a chemotherapeutic agent, is a checkpoint inhibitor.
48. The use of any one of claims 42 to 47, wherein the one or more therapeutic agents, e.g. chemotherapeutic agents, is a PD-1 inhibitor or a PD-L1 inhibitor, preferably the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
49. The use according to any one of claims 32 and 42 to 48, wherein Gevoglizumab or a functional fragment thereof is used alone or, preferably, in combination to prevent recurrence or recurrence of colorectal cancer in the patient after surgical removal of the cancer.
50. The use according to any one of claims 42 to 49, wherein Gevoglizumab or a functional fragment thereof alone or, preferably, in combination is used as a first, second or third line therapy for colorectal cancer.
51. The use of claim 32 or 42, wherein the one or more therapeutic agents, e.g., chemotherapeutic agents, is a standard of care agent for Renal Cell Carcinoma (RCC).
52. The use of claim 51, wherein the one or more therapeutic agents, e.g. chemotherapeutic agents, is a CTLA-4 checkpoint inhibitor, wherein preferably the CTLA-4 checkpoint inhibitor is epilimumab.
53. The use of claim 51 or 52, wherein the one or more therapeutic agents, such as a chemotherapeutic agent, is everolimus.
54. The use of any one of claims 51-53, wherein the one or more therapeutic agents, such as a chemotherapeutic agent, is a checkpoint inhibitor.
55. The use of any one of claims 51 to 54, wherein said one or more therapeutic agents, such as a chemotherapeutic agent, is a PD-1 inhibitor or a PD-L1 inhibitor, said PD-1 inhibitor or PD-L1 inhibitor preferably being selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
56. The use of any one of claims 51-55, wherein the one or more therapeutic agents, e.g., chemotherapeutic agent, is nivolumab.
57. The use of any one of claims 51-56, wherein the one or more therapeutic agents, e.g., chemotherapeutic agent, is nivolumab plus epilizumab.
58. The use of any one of claims 51-57, wherein the one or more therapeutic agents, e.g., chemotherapeutic agent, is cabozantinib.
59. The use of any one of claims 32, 42, 51 to 58, wherein gavoglizumab or a functional fragment thereof, alone or preferably in combination, is used to prevent the recurrence or recurrence of Renal Cell Carcinoma (RCC) in a patient after the cancer has been surgically removed.
60. The use according to any one of claims 32, 42, 51 to 59, wherein gemfibrozumab or a functional fragment thereof is used alone or, preferably, in combination for first, second or third line therapy of Renal Cell Carcinoma (RCC).
61. The use of claim 32 or 42, wherein the one or more therapeutic agents, such as a chemotherapeutic agent, is a standard of care agent for gastric cancer (including esophageal cancer).
62. The use of claim 61, wherein said one or more therapeutic agents, e.g. chemotherapeutic agents, is a mitotic inhibitor, preferably a taxane, wherein preferably said taxane is selected from paclitaxel and docetaxel.
63. The use of any one of claims 61-62, wherein the one or more therapeutic agents, e.g., chemotherapeutic agents, are paclitaxel and Remuselluzumab.
64. The use of any one of claims 61-63, wherein the one or more chemotherapeutic agents is a checkpoint inhibitor.
65. The use of any one of claims 61 to 64, wherein the one or more therapeutic agents, such as a chemotherapeutic agent, is a PD-1 inhibitor or a PD-L1 inhibitor, preferably the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of: nivolumab, lanolingzumab, alemtuzumab, dulvolumab, avizumab and sibatuzumab (PDR-001).
66. The use of any one of claims 61-65, wherein the one or more therapeutic agents, e.g., chemotherapeutic agent, is nivolumab.
67. The use of any one of claims 61-66, wherein the one or more therapeutic agents, e.g., chemotherapeutic agents, are nivolumab and epilimumab.
68. The use according to any one of claims 32, 42 or 61 to 67, wherein gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to prevent the recurrence or recurrence of the gastric cancer (including esophageal cancer) in a patient after removal by surgery.
69. The use according to any one of claims 32, 42 or 61 to 68, wherein gemfibrozumab or a functional fragment thereof, alone or preferably in combination, is used as a first, second or third line therapy for gastric cancer (including esophageal cancer).
Technical Field
The present invention relates to the use of IL-1 β binding antibodies or functional fragments thereof for the treatment and/or prevention of cancer having at least a partial basis for inflammation, such as the cancers described herein, e.g. lung cancer.
Background
Lung cancer is one of the most common cancers in men and women worldwide. Lung cancer is divided into two types: small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC). The types are distinguished by histological and cytological observations, with NSCLC accounting for approximately 85% of lung cancer cases. Non-small cell lung cancer is further divided into subtypes including, but not limited to, squamous cell carcinoma, adenocarcinoma, bronchoalveolar carcinoma, and large cell (undifferentiated) carcinoma. Despite the many treatment options, 5-year survival rates are only between 10% and 17%. Therefore, there remains a need to develop new treatment options for lung cancer.
Likewise, while current standard of care has provided significant improvement in outcome for other cancers with at least a partial basis for inflammation, the vast majority of patients who progress in chemotherapy have incurable disease with limited survival.
Disclosure of Invention
Other cancers that typically have at least a partial basis for inflammation include colorectal cancer (CRC), melanoma, gastric cancer (including esophageal cancer), Renal Cell Carcinoma (RCC), breast cancer, prostate cancer, head and neck cancer, bladder cancer, hepatocellular carcinoma (HCC), ovarian cancer, cervical cancer, endometrial cancer, pancreatic cancer, neuroendocrine cancer, hematologic cancer (particularly multiple myeloma, Acute Myeloid Leukemia (AML)), and biliary tract cancer.
In another aspect, the invention relates to a specific clinical dosage regimen directed to the administration of an IL-1 β binding antibody or functional fragment thereof for the treatment and/or prevention of a cancer having at least a partial basis for inflammation, such as a cancer described herein (e.g., lung cancer). in another aspect, a subject having a cancer having at least a partial basis for inflammation, including lung cancer, is administered one or more therapeutic agents (e.g., chemotherapeutic agents) in addition to the administration of an IL-1 β binding antibody or functional fragment thereof and/or has received/received a debulking procedure.
Also provided are methods of treating or preventing a cancer having at least a partial basis for inflammation, such as a cancer described herein (e.g., lung cancer), in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an IL-1 β binding antibody or functional fragment thereof.
Another aspect of the invention is the use of an IL-1 β binding antibody or a functional fragment thereof for the manufacture of a medicament for the treatment of a cancer having at least a partial basis for inflammation, such as a cancer as described herein (e.g. lung cancer).
The present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of an IL-1 β binding antibody or functional fragment thereof (suitably canargiunumab or gavage mab) for treating and/or preventing a cancer having at least a partial basis for inflammation, such as a cancer described herein (e.g., lung cancer) in a patient in certain aspects, IL-1 β binding antibody or functional fragment thereof is administered at a dose equal to or greater than 30mg per treatment in one aspect, the IL-1 β binding antibody or functional fragment thereof is canargiunumab and is administered at a dose of about 30mg to about 450mg per treatment, or at least 150mg per treatment, or at least 200mg per treatment, or 200mg to about 450mg per treatment in one aspect, the IL-1 β binding antibody or functional fragment thereof is gavage mab and is administered at a dose of about 30mg to 180mg per treatment, or about 60mg to 120mg per treatment in another aspect, such administration may be, for example, every two, three or three weeks, and may be administered in a lyophilized form for reconstitution in a liquid, intravenous, or monthly form.
The invention also relates to the use of a high sensitivity C-reactive protein (hsCRP) as a biomarker in the diagnosis, patient selection, and/or prognosis of a cancer (e.g. a cancer with at least a partial basis for inflammation) in a patient for the treatment and/or prevention of a cancer (including lung cancer) with at least a partial basis for inflammation the invention further relates to the use of a high sensitivity C-reactive protein (hsCRP) as a biomarker in the treatment and/or prevention of a cancer (including lung cancer) with at least a partial basis for inflammation in a patient, wherein the patient is treated with an IL-1 β inhibitor, an IL-1 β binding antibody or a functional fragment thereof (e.g. canargizumab or kuvacizumab) in a further aspect the invention relates to the use of a high sensitivity C-reactive protein (hsCRP) as a biomarker in the treatment and/or prevention of a cancer with at least a partial basis for inflammation in a patient, wherein the patient is treated with an IL-1 β inhibitor, an IL-1 β binding antibody or a functional fragment thereof (e.g. canargilizumab or a functional fragment thereof) in one aspect the patient is treated with an IL-1 β binding antibody or a functional fragment thereof (e.g. a antagonist or a functional fragment thereof) for example, e.1 or a fragment thereof) for a antagonist such as an IL-1- β binding antibody or a functional fragment thereof (e.5) for example, e.7 g. a reducing the patient's) for a reducing the level of IL-1 or a reducing the patient's binding antibody or a therapeutic antibody for a therapeutic effect after the patient's (e.7) for a therapeutic effect of a therapeutic effect.
In one aspect, the invention features a method of treating a human subject having a cancer with at least a partial basis for inflammation (e.g., a cancer such as lung cancer described herein) and an hsCRP level greater than or equal to 6mg/L, e.g., 10mg/L, 15mg/L, or 20mg/L, the method including administering to the subject a dose of IL-1 β binding antibody or a functional fragment thereof (e.g., canargizumab or gavaguzumab) in one embodiment, the IL-1 β antibody or a functional fragment thereof is administered at a dose described herein.
In one aspect, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., canargizumab or gavagizumab) for use in a male patient in need thereof to treat and/or prevent a cancer that has at least a partial basis for inflammation, e.g., a cancer described herein (e.g., lung cancer).
In one aspect, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., Kanagilumunumab or Gevojizumab) for use in a patient in need thereof to treat and/or prevent a cancer, e.g., a cancer having at least a partial basis for inflammation, e.g., a cancer described herein but not including lung cancer.
In one aspect, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., Cainajirimumab or Gevojizumab) for use in a patient in need thereof to treat and/or prevent a cancer that has at least a partial basis for inflammation, e.g., a cancer described herein but not including breast cancer.
In one aspect, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., Kanagiruzumab or Gevojizumab) for use in a patient in need thereof to treat and/or prevent a cancer that has at least a partial basis for inflammation, such as the cancers described herein, but not including lung cancer and colorectal cancer.
In one aspect, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., Kanagiruzumab or Gevojizumab) for use in a patient in need thereof to treat and/or prevent a cancer selected from the group consisting of lung cancer, particularly NSCLC, colorectal cancer (CRC), melanoma, gastric cancer (including esophageal cancer), Renal Cell Carcinoma (RCC), breast cancer, prostate cancer, head and neck cancer, bladder cancer, HCC, ovarian cancer, cervical cancer, endometrial cancer, pancreatic cancer, neuroendocrine cancer, multiple myeloma, Acute Myeloid Leukemia (AML), and biliary tract cancer.
Drawings
FIG. 1-CANTOS test spectra.
2-4. cumulative incidence of fatal cancer (FIG. 2), lung cancer (FIG. 3), and fatal lung cancer (FIG. 4) in CANTOS participants randomly assigned to placebo, 50mg of Canatkinumab, 150mg of Canatkinumab, or 300mg of Canatkinumab.
FIG. 5 Risk ratio forest plot (diagnosed lung cancer patients) -300mg vs placebo.
FIG. 6 median change from baseline for hsCRP at
FIG. 7. in vivo model of spontaneous human breast cancer metastasis to human bone predicts the critical role of IL-1 β signaling in breast cancer bone metastasis3Was subcutaneously implanted into 8-week-old female NOD SCID mice (n-10/group). Luciferase labelled MDA-MB-231-luc 2-Tdtomoto or T47D cells were injected into the post-mammary fat pad after 4 weeks. Each experiment was performed at three separate times, with each repetition performed using the bones of a different patient. The histograms show IL-1B, IL-1R1, caspase 1 and IL-1R compared to GAPDHFold change in copy number a (dCT), tumor cells grown in vivo compared to tumor cells grown in tissue culture flasks (a i), metastatic breast tumors compared to non-metastatic breast tumors (a ii), circulating tumor cells compared to tumor cells retained in fat pads (a iii), and bone metastases compared to matched primary tumors (a iv) fold change in IL-1 β protein expression is shown in (b) fold change in copy number of genes associated with EMT compared to GAPDH (E-cadherin, N-cadherin, and JUP) compared to primary bone, ═ P compared to primary bone<0.01**＝P<0.001，***＝P<0.0001，^^^＝P<0.001。
Fig. 8. stable transfection of breast cancer cells with IL-1B MDA-MB-231, MCF7 and T47D breast cancer cells with IL-1B using a human cDNA ORF plasmid with a C-terminal GFP tag or a control plasmid a) shows the effect of pg/ng IL-1 β protein from IL-1 β positive tumor cell lysate compared to a scrambled sequence control B) shows the effect of IL-1B overexpression on MDA-MB-231 and MCF7 cell proliferation by IL-1B overexpression from 10,000 IL-1 β + and control cells secreted IL-1 β measured by ELISA in (C and d), respectively, compared to scrambled sequence control, shown as mean values SEM, ═ P <0.01, ═ P <0.001, ═ P < 0.0001.
Fig. 9. tumor-derived IL-1 β induced epithelial to mesenchymal transformation in vitro MDA-MB-231, MCF7 and T47D cells were stably transfected to express high levels of IL-1B, or to transfect scrambled sequences (controls) to assess the effect of endogenous IL-1B on parameters associated with metastasis. elevated endogenous IL-1B resulted in a change of tumor cells from epithelial to mesenchymal phenotype (a). B) showed copy number and fold change in protein expression of IL-1B, IL-1R1, E-cadherin, N-cadherin and JUP compared to GAPDH and β -catenin, respectively, (c) showed the ability of tumor cells to invade osteoblasts through stroma glue and/or 8 μ M pores, and the ability of cells to migrate within 24 and 48 hours using a wound closure assay (d). data are shown as mean +/-SEM, <0.01, < P > 001.0001.
FIG. 10 pharmacological blockade of IL-1B inhibits spontaneous metastasis to human bone in vivo. Carrying two blocks of 0.5cm3Female NOD-SCID mice of human femur injected with MDA-MB-231Luc2-Tdtomato cells in the udder. One week after tumor cell injection, mice were treated with 1 mg/kg/day IL-1Ra, 20mg/kg/14 day canarginoumab or placebo (control) (n-10/group). All animals were picked 35 days after tumor cell injection. The effect on bone metastasis was assessed in vivo by luciferase imaging and immediately after autopsy (a) and confirmed ex vivo on tissue sections. Data are shown as the number of photons emitted per second 2 minutes after subcutaneous injection of D-luciferin. (b) Shows the effect on the number of tumor cells detected in the circulation. P ═ P<0.01，**＝P<0.001，***＝P<0.0001。
FIG. 11 tumor-derived IL-1B promotes bone homing of breast cancer in vivo. Female BALB/c
Fig. 12. tumor cell-bone cell interaction stimulates IL-1B producing cell proliferation MDA-MB-231 or T47D human breast cancer cell line was cultured alone or in combination with live human bone, HS5 bone marrow cells or OB1 primary osteoblasts a) shows the effect of culturing MDA-MB-231 or T47D cells in a live human bone disc on the concentration of IL-1 β secreted into the culture medium B) and c) show the effect of co-culturing MDA-MB-231 or T47D cells with HS5 bone cells on IL-1 β derived from individual cell types after cell sorting and on proliferation of these cells d) shows the effect of co-culturing MDA-MB-231 or T47D cells with OB1 (osteoblasts) on proliferation.
Figure 13. IL-1 β in bone microenvironment stimulates expansion of bone metastasis microenvironment (a) shows the effect of addition of 40pg/ml or 5ng/ml recombinant IL-1 β to MDA-MB-231 or T47D breast cancer cells, and B) and C) show the effect of addition of 20pg/ml, 40pg/ml or 5ng/ml IL-1B on HS5, bone marrow or OB1 osteoblast proliferation, respectively, (d) after CD34 staining in the tibial trabecular region from 10-12 week old female IL-1R1 knockout mice, IL-1 driven bone vascular alterations were measured (e) 31 day BALB/C nude mice were treated with 1 mg/ml/day IL-1Ra, and (f) 4-96 hour C57BL/6 mice treated with 10 μ M canargimab-data show an average value of 0.01P ═ 0.001 ═ P ═ 0.0001.
FIG. 14 inhibition of IL-1 signaling affects bone integrity and blood vessels. Tibia and sera from mice that do not express IL-1R1(IL-1R1KO), BALB/C nude mice treated with 1mg/kg of IL-1R antagonist daily for 21 days and 31 days, and C57BL/6 mice treated with 10mg/kg of canarginia mab (Ilaris) for 0-96 hours were analyzed for: bone integrity was analyzed by μ CT and blood vessels were analyzed by ELISA for endothelin 1 and pan VEGF. a) The effect of IL-1R1KO is shown; b) the effect of anakinra, and c) the effect of canarginoumab on bone volume compared to tissue volume (i), the concentration of endothelin 1 (ii), and the concentration of VEGF secreted into the serum. Data shown are mean values +/-SEM, ═ P <0.01, ═ P <0.001, ═ P <0.0001 compared to controls.
FIG. 15. tumor-derived IL-1 β predicts future relapse and bone relapse in patients with stage II and III breast cancer.Primary breast cancer samples from about 1300 patients with stage II and III breast cancer with no evidence of metastasis were stained for 17kD active IL-1 β. tumors were scored for IL-1 β in the tumor cell population the data shown is a Kaplan Meyer curve showing the correlation between tumor-derived IL-1 β and subsequent relapse at any site a) or b) in bone over a 10 year period.
FIG. 16 simulation of Kanagilunumab PK profiles and hscRP profiles. a) The canargiunumab concentration time spectrum is shown. Solid line and band: median values for each simulated concentration were predicted at intervals of 2.5% -97.5% (300mg Q12W (bottom line), 200mgQ3W (middle line), and 300mg Q4W (top line)). b) The ratio of hsCRP to below the critical point of 1.8mg/L at
FIG. 17 Gene expression analysis by RNA sequencing of colorectal cancer patients receiving PDR001 in combination with Kanagiruzumab, PDR001 in combination with everolimus and PDR001 in combination with others. In the figure of the heatmap, each row represents the RNA level of the marker gene. Patient samples are depicted by vertical lines, screen (pre-treatment) samples are shown in the left column, and cycle 3 (treatment) samples are shown in the right column. The RNA levels of each gene were normalized by row, with black indicating samples with higher RNA levels and white indicating samples with lower RNA levels. Neutrophil-specific genes FCGR3B, CXCR2, FFAR2, OSM and G0S2 are boxed.
Figure 18 clinical data after treatment with gemtuzumab ozogamicin (group a) and its extrapolation to higher doses (groups b, c and d). a) Percent change in adjustment of hsCRP from baseline in the patient. b) Six different hsCRP baseline concentrations are shown for hsCRP exposure response relationships. b) And c) shows the simulation of two different doses of gemtuzumab ozogamicin.
FIG. 19. Effect of anti-IL-1 β treatment in two cancer mouse models A), b), and c) show data from the MC38 mouse model, d) and e) show data from the LL2 mouse model.
Detailed Description
The appearance of many malignancies in areas of chronic inflammation (1), and the lack of regression of inflammation is believed to play a major role in tumor invasion, progression and metastasis (2-4) inflammation has a particular pathophysiological relevance to lung cancer, where chronic bronchitis triggered by asbestos, silica, smoking and other external inhaled toxins leads to a persistent pro-inflammatory response (5, 6) the inflammatory activation in the lung is mediated in part by the activation of the Nod-like receptor protein 3(NLRP3) inflammasome and subsequent local production of interleukin-1 β (IL-1 β), which can lead to chronic fibrosis and cancer (7, 8) in murine models, inflammatory body activation and IL-1 β production can accelerate tumor invasion, growth and metastatic spread (2) for example, in IL-1 β -/-mice, after local or intravenous vaccination with a melanoma cell line, there are neither local tumors nor lung metastases, data suggest that IL-1 β may have a crucial role in the treatment of existing malignancies (9-1 β) in this cancer treatment, which may be due to at least partial inhibition of inflammation by IL-1-8513.
The present invention results at least in part from analysis of data generated by a CANTOS assay, which is a randomized, double-blind, placebo-controlled, event-driven assay. CANTOS aims to assess whether subcutaneous administration of canargizumab quarterly can prevent recurrence of cardiovascular events in patients after stable myocardial infarction with elevated hsCRP. The 10,061 patients enrolled with myocardial infarction and inflammatory atherosclerosis had no previously diagnosed cancer and had a high sensitivity C-reactive protein (hsCRP) of ≧ 2 mg/L. Three incremental canarginoumab doses (50 mg, 150mg, and 300mg administered subcutaneously every 3 months) were compared to placebo. Participants were diagnosed for sporadic cancer over an average follow-up period of 3.7 years.
The patient population is eligible for CANTOS participation if the patient has a past history of myocardial infarction and hscRP levels in the blood are greater than or equal to 2mg/L despite the use of an aggressive secondary prevention strategy. Since canargiunumab is a systemic immunomodulator, the aim of this trial was to exclude patients with a history of chronic or recurrent infection, previous malignancies other than basal cell skin cancer, suspected or known low immune function, a history or high risk of tuberculosis or HIV-related disease, or ongoing use of systemic anti-inflammatory therapy from enrollment.
Randomization (fig. 1) based on the experience of phase IIb study (19), an "anchor dose" of 150mg SC per three months was initially selected for canarginoumab, hi addition, a high dose of 300mg administered twice within two weeks and then once per three months was also initially selected to address the theoretical issue of IL-1 β self-induction, therefore, upon screening the first patient at 11 days 4-2011, CANTOS began as a three-group trial, a standard-care placebo was compared to either 150mg of standard-care canarginoumab or 300mg of canarginoumab, and participants were assigned to each study group at a 1:1:1 ratio, however, a lower dose of the canarginou group was introduced into the trial (50 mg SC per three months) based on the health authorities' feedback that more extensive dose response data was required, thus, revising the protocol and approving the formal four-month 7-month structures in year, but using different times in 2011 and regions.
To accommodate this structural variation, the proportion of individuals that will ultimately be assigned to placebo increases as the proportion of individuals that will be randomly assigned to the 50mg dose varies. Thus, the treatment allocation ratio was changed from 1:1:1 placebo to 150mg canarginoumab to 300mg canarginoumab of the 741 participants enrolled for the first batch to 2:1.4:1.3:1.3 placebo to 50mg canarginoumab to 150mg canarginoumab to 300mg canarginoumab of the remaining 9,320 participants, respectively. Trial enrollment was completed in 3 months 2014 and all participants followed up to 5 months 2017.
According to protocol, all CANTOS participants performed whole blood cell counts, blood lipid panel tests, hsCRP, and renal and hepatic function measurements at 3, 6, 9, 12, 24, 36, and 48 months after baseline and randomization.
Endpoint the clinical endpoint of interest of the assay is any sporadic cancer diagnosed and reported during the trial follow-up. For any such event, medical records were obtained and cancer diagnosis was reviewed by a panel of oncologists unaware of study drug distribution. Where possible, the primary source should be noted, as well as any evidence of metastasis at a particular site. The endpoint committee of the experiment also classified cancer as fatal or non-fatal.
Statistical analysis the Cox proportional hazards model was used to analyze the overall cancer incidence for the canargiunumab and placebo groups, as well as the incidence of both fatal and non-fatal cancers, as well as the incidence of cancer at specific sites. For the purposes of proof of concept, and consistent with analysis of all data and safety monitoring board meetings throughout the course of the experiment, comparisons were made between the incidence at placebo and the incidence of each of the canarginous mab doses alone, the incremental canarginous mab doses (scores of 0, 1, 3, and 6 proportional to dose), and the combination activated canarginous mab treatment groups.
Results
CANTOS showed compliance with the primary endpoint, suggesting that cana geminumab (also known as ACZ885), when combined with standard of care, may reduce the risk of Major Adverse Cardiovascular Events (MACE) in patients with prior heart attacks and inflammatory atherosclerosis. MACE is a complex of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. It has been demonstrated that ACZ885 can reduce cardiovascular risk in people who have previously suffered a heart disease by selectively targeting inflammation.
Patients those with or without cancer diagnosis during the trial follow-up are provided with a baseline clinical profile of 10,061 CANTOS participants in table 1.
Patients who develop sporadic lung cancer are older (P <0.001) and more likely to be current smokers (P <0.001) than patients who have not been diagnosed with cancer. Consistent with previous work showing that some cancers have a strong inflammatory component, the median level of hsCRP was higher at baseline in people diagnosed with lung cancer during follow-up than in people without any cancer diagnosis (6.0 vs. 4.2mg/L, P < 0.001). Similar data were observed for interleukin-6 (3.2 vs. 2.6ng/L, P < 0.0001).
During the trial follow-up, canargizumab was associated with the following compared to placebo: hsCRP dose-dependent decreases by 27% to 40% (all P values <0.0001), whereas IL-6 dose-dependent decreases by 25% to 43% (all P values < 0.0001). Canarginoumab had no effect on LDL or HDL cholesterol.
Effect on total and fatal cancer events the incidence of any cancer in the placebo, 50mg, 150mg, and 300mg canarginoumab groups was 1.84, 1.82, 1.68, and 1.72, respectively, per 100 human years (P ═ 0.34 across the canarginoumab dose group compared to placebo). In contrast, a statistically significant dose-dependent effect was observed for the lethal cancer, with the incidence rates in the placebo, 50mg, 150mg and 300mg groups of 0.64, 0.55, 0.50 and 0.31 (P ═ 0.001 across canarginoumab dose groups compared to placebo, respectively) per 100 human years (table 2).
Effect on lung cancer random assignment to canarginoumab was associated with a statistically significant dose-dependent decrease in overall cancer mortality during the median 3.7 year follow-up period. For this endpoint (N-196), the hazard ratios (95% confidence interval, P-value) for the canarginoumab 50mg, 150mg and 300mg groups were 0.86(0.59-1.24, P-0.42), 0.78(0.54-1.13, P-0.19) and 0.49(0.31-0.75, P-0.0009), respectively, with reference to placebo. These data correspond to the incidence of 0.64, 0.55, 0.50 and 0.31 per 100 years in the placebo, 50mg, 150mg and 300mg groups, respectively (P ═ 0.0007 across the active dose group compared to the placebo) (table 2 and figure 2).
This effect is mainly due to the reduction of lung cancer; lung cancer accounts for 26.0% of all cancers and 47% of all cancer deaths in patients assigned to placebo, while lung cancer accounts for 16% of all cancers and 34% of cancer deaths in patients assigned to canarginoumab. For sporadic lung cancer (N ═ 129), the risk ratios (95% confidence interval, P values) for the canajirimumab 50mg, 150mg and 300mg groups were 0.74(0.47-1.17, P ═ 0.20), 0.61(0.39-0.97, P ═ 0.034) and 0.33(0.18-0.59, P ═ 0.0001), respectively, with reference to placebo. These data correspond to the incidence of 0.49, 0.35, 0.30 and 0.16 per 100 human years for the placebo, 50mg, 150mg and 300mg groups, respectively (P <0.0001 across the active dose group compared to placebo) (table 2 and figure 3).
Smoking stratification shows that the relative benefit of canarginoumab in current smokers for lung cancer is slightly greater than in past smokers (current smoker HR 0.50, P ═ 0.005; past smoker HR0.61, P ═ 0.006). This effect was more pronounced for the highest canarginoumab dose (current smoker HR 0.25, P ═ 0.002; past smoker HR 0.44, P ═ 0.025, table S2).
For lung cancer mortality (N ═ 77), the risk ratios (95% confidence interval, P value) for the canajirimumab 50mg, 150mg and 300mg groups were 0.67(0.37-1.20, P ═ 0.18), 0.64(0.36-1.14, P ═ 0.13) and 0.23(0.10-0.54, P ═ 0.0002), respectively, with reference to placebo. These data correspond to an incidence of 0.30, 0.20, 0.19 and 0.07 per 100 human years for the placebo, 50mg, 150mg and 300mg groups, respectively (P ═ 0.0002 across the active dose group compared to the placebo) (table 2 and figure 4).
The benefits of canarginoumab were evident in patients with unspecified lung cancer type or histologically manifested adenocarcinoma or poorly differentiated large cell carcinoma (placebo, 50mg, 150mg and 300mg dose groups with incidence rates of 0.41, 0.33, 0.27 and 0.12 respectively [ trend P across dose groups 0.0004 compared to placebo ] in cases histologically manifested small cell lung cancer or squamous cell carcinoma, capacity was limited to the effects of specifically described canarginoumab (table S3).
In the analysis of the combined canarginoumab dose, those patients whose hsCRP decreased by greater than or equal to the median value at 3 months had a greater reduction in the risk of total lung cancer. Specifically, the observed lung cancer risk ratio in humans achieving a hsCRP reduction greater than 1.8mg/L median at 3 months compared to placebo was 0.29 (95% CI 0.17-0.51, P <0.0001), which is superior to those observed effects of hsCRP reduction less than median (HR 0.83, 95% CI 0.56-1.22, P ═ 0.34). A similar effect was observed for the median IL-6 level reached at 3 months.
Although the CANTOS protocol was intended to exclude individuals with past non-basal cell malignancies, 76 of 10,061 patients (0.8%) were found to have past cancers in a scrutiny. The post-exclusion of these individuals had no effect on the above results.
Adverse events were rare with respect to bone marrow function, thrombocytopenia and neutropenia, but were more common in patients assigned to canarginia mab (table 3) as reported elsewhere (20), although there was no increase in total infection rate, combining the three canarginia mab groups and comparing to placebo, the incidence of cellulitis and clostridium difficile colitis increased, and the incidence of fatal events due to infection or sepsis increased (0.31 for incidence per 100 people compared to 0.18, P ═ 0.023.) participants who died from infection tended to be older, and more likely to have diabetes mellitus.) despite this adverse effect, the non-cardiovascular mortality rates (HR 0.97, 95% CI 0.79-1.19, P ═ 0.80) and the total-cause mortality rates (HR 0.94, 95% CI0.83-1.06, P ═ 0.31) both decreased non-significantly in both the canarginia mab and placebo groups and the incidence of severe gout inhibition (similar for the incidence of arthritis) was reported to be similar to the incidence of osteoarthritis, the placebo group, and the incidence of osteoarthritis was similar to the incidence of severe gout.
In these randomized, double-blind, placebo-controlled experimental data, the median time of inhibition of IL-1 β for 3.7 years using canaryknumab significantly reduced the incidence of fatal and non-fatal lung cancer in atherosclerotic patients with elevated hsCRP without a prior diagnosis of cancer in patients randomly assigned to the highest canaryknumab dose (300mg SC every 3 months), the relative risk of total and fatal lung cancer decreased by 67% (P ═ 0.0001) and 77% (P ═ 0.0002), respectively, with the effect being dose-dependent.
CANTOS is an inflammation reduction test (17) for patients after myocardial infarction with elevated hsCRP and high current or past smoking rates these features increase the risk of CANTOS population for lung cancer above the mean risk and provide the study with the additional opportunity reported herein to study the effects of interleukin-1 β inhibition on cancer.
Although possible, canarginoumab is unlikely to have any direct effect on tumorigenesis and the development of new lung cancer. Patients with lung cancer during follow-up were 65 years of age on average at study start, with over 90% being current or past smokers. Furthermore, the mean follow-up time may not be sufficient to demonstrate a reduction in new cancers.
In contrast, it seems more likely that canargizumab (a potent inhibitor of interleukin-1 β) significantly reduced the rate of progression, invasiveness and metastatic spread of lung cancer that is ubiquitous at the start of the trial, but not diagnosed in this regard, clinical data are consistent with prior experimental work, suggesting that cytokines such as IL-1 β may promote angiogenesis and tumor growth, and that IL-1 β is essential for tumor invasion of already existing malignant cells (2-4, 9). in murine models, high IL-1 β concentrations in the tumor microenvironment are associated with a stronger phenotype (13), and secreted IL-1 β originating from this microenvironment (or directly from malignant cells) may promote tumor invasiveness and in some cases induce tumor-mediated inhibition (2, 9, 21).
This microenvironment is believed to consist of three interacting microenvironments, osteoblasts, blood vessels and hematopoietic stem cells (reviewed by Massague and Obenauf, 2016; weilbaceher et al, 2011). evidence from metastasis in other organs suggests that proliferation of vascular endothelial cells and the appearance of new blood vessels may also promote proliferation of tumor cells in the formation of bone-driven metastases (Carbonell et al, 2009; kineast et al, 2010), previously shown that, compared to parental MDA-MB-231 cells, skeletal breast cancer cell line MDA-IV produces high concentrations of IL-1 β (Nutter et al, 2014), as well as, in the 3 model of prostate cancer, overexpression of IL-PC-1 β increases gene metastasis of cardiac tumor cells, while knock-out bone metastases of such molecules (liuu et al, 2013).
Since the Virchow age, inflammation has been associated with cancer, as written by Balkwill and Mantovani,' if the gene damage is the cancer "match to ignite a fire," certain types of inflammation may provide "flame-promoting fuels" (22). this hypothesis helps explain in part why long-term use of aspirin and other non-steroidal anti-inflammatory drugs has been associated with reduced mortality of colorectal and lung adenocarcinoma (23, 24). however, in contrast to these drugs which require ten or more years of use to show efficacy, the beneficial effects of Caragavacizumab on lung cancer incidence and lung cancer mortality have been observed in a shorter time frame trial, in a few weeks of treatment initiation.
This test was not designed for cancer treatment studies, rather, by design, it recruited atherosclerotic patients with no previous history of cancer.this approach to IL-1 targeted cytokines against other cancer types has precedent.e.g., the IL-1 receptor antagonist anakinra has been reported to moderately reduce the progression of stasis or indolent myeloma in the case of 47 patients (25). in the second case of 52 patients with various metastatic cancers, human monoclonal antibodies targeting IL-1 α have good tolerance and show modest improvements in lean body mass, appetite, and pain (26).
In summary, these randomized placebo-controlled experimental data provide evidence that inhibition of innate immune function with canargizumab (a monoclonal antibody targeting IL-1 β) significantly reduces lung cancer incidence and lung cancer mortality.
Thus, in one aspect, the invention provides the use of an IL-1 β binding antibody or a functional fragment thereof (the term "IL-1 β binding antibody or a functional fragment thereof" is sometimes referred to herein as "the medicament of the invention", which is to be understood as the same term), suitably canargizumab or a functional fragment thereof (comprised in the medicament of the invention), suitably worguzumab or a functional fragment thereof (comprised in the medicament of the invention), for the treatment and/or prevention of a cancer that has at least a partial basis for inflammation (e.g. the cancer described herein, including but not limited to lung cancer).
In one embodiment, the cancer is lung cancer, and the lung cancer has concomitant inflammation activation or inflammation mediated in part by Nod-like receptor protein 3(NLRP3) inflammatory-body activation and thereby causing the production of local interleukin-1 β.
One of the major inflammatory pathways that support tumor development and progression is IL-1 β, which is a pro-inflammatory cytokine produced by tumor and tumor-associated immunosuppressive cells, including neutrophils and macrophages in the tumor microenvironment.
Accordingly, the present disclosure provides methods of treating cancer using IL-1 β binding antibodies or functional fragments thereof, wherein such IL-1 β binding antibodies or functional fragments thereof may reduce inflammation and/or improve tumor microenvironment, e.g., may inhibit IL-1 β -mediated inflammation and IL-1 β -mediated immunosuppression in a tumor microenvironment.
As used herein, "cancer" is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues, or malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasion. Examples of cancerous diseases include, but are not limited to, solid tumors, hematologic cancers, soft tissue tumors, and metastatic lesions. Examples of solid tumors include malignancies, such as sarcomas and carcinomas (including adenocarcinomas and squamous cell carcinomas), of various organ systems, such as those affecting the liver, lung, breast, lymph, gastrointestinal (e.g., colon), genitourinary tract (e.g., kidney cells, urothelial cells), prostate and pharynx. Adenocarcinoma includes malignancies such as most colon, rectal, renal cell, liver, non-small cell lung, small intestine and esophageal cancers. Squamous cell carcinoma includes, for example, malignant tumors in the lung, esophagus, skin, head and neck regions, oral cavity, anus, and cervix. In one embodiment, the cancer is melanoma, e.g., advanced melanoma. The methods and compositions of the present invention may also be used to treat or prevent metastatic disease of the above-mentioned cancers.
Exemplary cancers whose growth can be inhibited using the antibody molecules disclosed herein include cancers that are generally responsive to immunotherapy. Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer). In addition, antibody molecules described herein can be used to treat refractory or recurrent malignancies.
Examples of other cancers that may be treated include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastroesophageal cancer, gastric cancer, liposarcoma, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Merkel (Merkel) cell carcinoma, hodgkin's lymphoma, non-hodgkin's lymphoma, esophageal cancer, small bowel cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, cancer of the urethra, cancer of the penis, chronic or acute leukemia (including acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), solid tumors of childhood, lymphocytic lymphoma, bladder cancer, multiple myeloma, myelodysplastic syndrome, Renal or ureteral cancer, renal pelvis cancer, central nervous system tumors (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's (Kaposi) sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally-induced cancers including asbestos-induced cancers (e.g., mesothelioma), and combinations of said cancers. In certain embodiments, the cancer is a skin cancer, such as merkel cell carcinoma or melanoma. In one embodiment, the cancer is merkel cell carcinoma. In other embodiments, the cancer is melanoma. In other embodiments, the cancer is breast cancer, e.g., Triple Negative Breast Cancer (TNBC) or HER2 negative breast cancer. In other embodiments, the cancer is a renal cancer, such as a renal cell carcinoma (e.g., Clear Cell Renal Cell Carcinoma (CCRCC) or non-clear cell renal cell carcinoma (ncrcc)). In other embodiments, the cancer is thyroid cancer, e.g., Anaplastic Thyroid Cancer (ATC). In other embodiments, the cancer is a neuroendocrine tumor (NET), such as atypical lung carcinoid or NET in the pancreas, gastrointestinal tract (GI), or lung. In certain embodiments, the cancer is lung cancer, e.g., non-small cell lung cancer (NSCLC) (e.g., squamous NSCLC or non-squamous NSCLC). In certain embodiments, the cancer is leukemia (e.g., Acute Myeloid Leukemia (AML), such as relapsed or refractory AML or primary AML). In certain embodiments, the cancer is myelodysplastic syndrome (MDS) (e.g., high risk MDS).
In some embodiments, the cancer is selected from lung cancer, squamous cell lung cancer, melanoma, renal cancer, liver cancer, myeloma, prostate cancer, breast cancer, ER + breast cancer, IM-TN breast cancer, colorectal cancer, high microsatellite instability colorectal cancer, EBV + gastric cancer, pancreatic cancer, thyroid cancer, hematological cancer, non-hodgkin lymphoma, or leukemia, or a metastatic lesion of the cancer. In some embodiments, the cancer is selected from non-small cell lung cancer (NSCLC), NSCLC adenocarcinoma, NSCLC squamous cell carcinoma, or hepatocellular carcinoma.
The meaning of "cancer having at least a partial basis for inflammation" or "cancer having at least a partial basis for inflammation" is well known in the art and as used herein refers to any cancer in which an IL-1 β mediated inflammatory response contributes to tumor development and/or spread (including but not limited to metastasis). such cancers typically have a concomitant inflammatory activation or inflammation mediated in part by Nod-like receptor protein 3(NLRP3) inflammatory corpuscle activation and thereby causing local interleukin-1 β production in patients with such cancer, expression or even overexpression of IL-1
Inhibition of IL-1 β results in a reduction in inflammatory states, including but not limited to reduced levels of hsCRP or IL-6 in particular, the present invention has for the first time shown that the effect is associated with the efficacy of a treatment for cancer (e.g., lung cancer).
The term "cancer having at least a partial basis for inflammation (cancer that has had at least partial least one partial inflammation associated with a partial inflammation associated with.
Available techniques known to those skilled in the art allow the detection and quantification of IL-1 β in tissue as well as serum/plasma, particularly when IL-1 β is expressed above normal levels, for example, IL-1 β cannot be detected in most healthy donor serum samples using the high sensitivity IL-1b ELISA kit from R & D systems, as shown in the following table.
Sample value
Serum/plasma-samples from apparently healthy volunteers were evaluated in this assay for the presence of human IL-1 β.
ND is undetectable
Thus, according to the present test, using a high sensitivity R & D Il-1 β ELISA kit, Il-1 β levels in healthy humans are barely detectable or slightly above the detection limit it is expected that in cancer patients with at least a partial basis for inflammation, Il-1 β levels thereof are generally higher than normal and can be detected by the same kit, with a normal level (reference level) of Il-1 β expression in healthy humans, the term "Il-1 β" higher than normal refers to Il-1 β levels higher than the reference level, typically at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold higher than the normal level, blocking the Il-1 β pathway will generally trigger compensatory mechanisms leading to more Il-1 β production, thus the term "Il-1 β higher than normal level" also means and includes Il-1 β binding antibody or fragment thereof or more preferably Il-1- β levels in addition to Il-1- β administration prior to the cancer treatment, thus also leading to the Il-1- β level being higher than the normal (e.g. IL-1- β) level of the treatment agent.
The term "above normal level of IL-1 β" when used to detect IL-1 β expression in tissue preparations using staining (e.g., immunostaining) means that the staining signal generated by a specific IL-1 β protein or IL-1 β RNA detector molecule is significantly stronger than the staining signal of surrounding tissues that do not express IL-1 β.
As used herein, the terms "treatment" and "treating" refer to a reduction or alleviation of the progression, severity, and/or duration of a disorder (e.g., a proliferative disorder) or the alleviation of one or more symptoms (suitably one or more discernible symptoms) of a disorder resulting from the administration of one or more therapies. In particular embodiments, the terms "treat", "treating" and "treatment" refer to ameliorating at least one measurable physical parameter of a proliferative disorder, such as tumor growth, which is not necessarily discernible by the patient. In other embodiments, the terms "treat", "treating" and "treating" refer to inhibiting the progression of a proliferative disorder, either physically, by, for example, stabilizing a discernible symptom, physiologically, by, for example, stabilizing a physical parameter, or both. In other embodiments, the terms "treat", "treating" and "treating" refer to reducing or stabilizing tumor size or cancer cell count. For the cancers discussed herein, the term treatment refers to at least one of the following, exemplified by lung cancer: reducing one or more symptoms of lung cancer, delaying progression of lung cancer, reducing tumor size in a lung cancer patient, inhibiting lung cancer tumor growth, extending overall survival, extending progression-free survival, preventing or delaying metastasis of lung cancer tumors, reducing (e.g., eradicating) preexisting lung cancer tumor metastasis, reducing the incidence or burden of preexisting lung cancer tumor metastasis, or preventing recurrence of lung cancer.
In one embodiment, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., canargizumab or gavaglizumab) for use in the treatment and/or prevention of lung cancer, wherein the incidence of lung cancer is reduced by at least 30%, at least 40%, or at least 50% as compared to a patient not receiving such treatment.
Lung cancer includes small cell lung cancer and non-small cell lung cancer (NSCLC)/non-small cell lung cancer (NSCLC). NSCLC is any type of epithelial lung cancer other than Small Cell Lung Cancer (SCLC) and can be classified as squamous (about 30%) or non-squamous (about 70%; including adenocarcinoma and large cell histology) histological types. The term "NSCLC" includes, but is not limited to, lung adenocarcinoma (referred to herein as "adenocarcinoma"), poorly differentiated large cell carcinomas, squamous cell (epidermoid) lung carcinoma, adenosquamous carcinoma and sarcomatoid carcinoma, and bronchioloalveolar carcinoma. Lung cancer also includes metastasis to lung cancer and small cell lung cancer. In one embodiment of the invention, the lung cancer is small cell lung cancer. In another embodiment, the lung cancer is NSCLC. In one embodiment, the lung cancer is lung adenocarcinoma. In another embodiment, the lung cancer is large cell carcinoma poorly differentiated in the lung. In another embodiment, the lung cancer is non-squamous lung cancer. In another embodiment of the invention, the lung cancer is squamous cell (epidermoid) lung cancer. In yet another embodiment, the lung cancer is selected from the group consisting of adenosquamous carcinoma or sarcomatoid carcinoma or metastasis to lung cancer.
NSCLC is staged according to established guidelines, such as the AJCC cancer staging manual 8 th edition new york: spamming press; 2017, summarized by Goldstraw P et al The IASLC lung cancer stage project, of course for The review of The TNM stage groups in The for The study (elevation) evaluation of The TNM classification for The lung cancer stage project of IASLC: recommendations for revising TNM staging groups in the upcoming published (8 th edition) lung cancer classification Journal of clinical Oncology 2016; 11(1):39-51). Stage I is characterized by a local tumor, which has not spread to any lymph nodes. Stage II is characterized by a localized tumor that has spread to lymph nodes contained within the peripulmonary portion. Generally, stage I or II are considered to be early stages, as they show a size and location suitable for surgical resection.
Stage III is characterized by a localized tumor that has spread to regional lymph nodes not contained in the lung, such as mediastinal lymph nodes. Stage III is further divided into two sub-stages: stage IIIA, in which lymph node metastasis is on the same side of the lung as the primary tumor; stage IIIB, where the cancer has spread to the contralateral lung, to the lymph nodes above the clavicle, to the fluid surrounding the lung, or where the cancer grows into an important structure of the chest. Stage IV is characterized by the spread of the cancer to different parts of the lung (lobes) or to distant locations in the body, for example to the brain, bone, liver and/or adrenal glands.
In a preferred embodiment, the patient has early stage lung cancer, particularly NSCLC. In a preferred embodiment, the patient is diagnosed with lung cancer after an imaging-based lung cancer screening. In another embodiment, the lung cancer is advanced, metastatic, relapsed and/or refractory lung cancer. In one embodiment, the patient has stage IA NSCLC. In one embodiment, the patient has stage IB NSCLC. In one embodiment, the patient has stage IIA NSCLC. In one embodiment, the patient has stage IIB NSCLC. In one embodiment, the patient has stage IIIA NSCLC. In one embodiment, the patient has stage IIIB NSCLC. In another embodiment, the patient has stage IV NSCLC.
In one embodiment, the patient is a smoker, including current smokers and past smokers. The CANTOS test data is consistent with the general idea that smokers have a higher incidence of lung cancer than non-smokers. Although the risk ratio of current and past smokers was reduced in the treatment group compared to the placebo group, the smoking stratification showed a greater relative benefit of canarginoumab in current smokers for lung cancer compared to past smokers (current smoker HR 0.50, P ═ 0.005; past smoker HR0.61, P ═ 0.006). In the CANTOS test, current smokers are defined in particular as persons who smoke within the last 30 days at the time of screening. Past smokers were defined as persons who smoked before the time of screening but not within the past 30 days.
In one embodiment, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., Canatkinumab or Gevojizumab) for use in the treatment and/or prevention of lung cancer, wherein the incidence of lung cancer in a smoker is reduced by at least 30%, at least 40%, or at least 50% compared to a smoker who does not receive such treatment.
In one embodiment, the subject is a male patient with lung cancer. In one embodiment, the male patient is a current or past smoker.
In one embodiment, the invention provides the use of an IL-1 β binding antibody or a functional fragment thereof, suitably Canaguirnumab or a functional fragment thereof, Gevojizumab or a functional fragment thereof, to treat and/or prevent cancer, such as cancer with at least a partial basis for inflammation, including but not limited to lung cancer, in a patient with higher than normal levels of C-reactive protein (hsCRP), in another embodiment, the patient is a smoker, in another embodiment, the patient is a current smoker.
Higher than normal levels of C-reactive protein (hsCRP) are particularly reported in (including but not limited to) lung cancer (particularly NSCLC), colorectal cancer, melanoma, gastric cancer (including esophageal cancer), Renal Cell Carcinoma (RCC), breast cancer, hepatocellular carcinoma (HCC), prostate cancer, bladder cancer, AML, multiple myeloma, and pancreatic cancer.
As used herein, "C-reactive protein" and "CRP" refer to serum or plasma C-reactive protein, which is typically used as an indicator of the acute phase response of inflammation. However, in chronic diseases such as cancer, CRP levels may be elevated. CRP levels in serum or plasma can be given in any concentration, e.g., mg/dl, mg/L, nmol/L. The level of CRP can be measured by a variety of well-known methods, such as radioimmunodiffusion, electroimmunoassay, immunoturbidimetry (e.g., particle (e.g., latex) -enhanced turbidimetric immunoassay), ELISA, turbidimetry, fluorescence polarization immunoassay, and laser turbidimetry. The CRP test may employ a standard CRP test or a high sensitivity CRP (hscrp) test (i.e., a high sensitivity test capable of measuring lower levels of CRP in a sample by using immunoassay or laser turbidimetry). Kits for detecting CRP levels are commercially available from a variety of companies, such as Carl Biotechnology Inc. (Calbiotech Inc.), Karman Chemical Inc. (Cayman Chemical), Roche Diagnostics Inc. (Roche Diagnostics Corporation), Abazyme, DADE Behring, Abnova Inc., Anaira Inc., Bio-QuantInc., Siemens Healthcare Diagnostics, Yaya laboratories Inc. (Abbott laboratories), and the like.
As used herein, the term "hsCRP" refers to the level of CRP in blood (serum or plasma) as measured by the high sensitivity CRP test. For example, a Tina quantitative C-reactive protein (latex) high sensitivity assay (roche diagnostics) can be used to quantify hsCRP levels in a subject. Can be at
Each local laboratory will use a threshold value for abnormal (high) CRP or hsCRP according to the rules for calculating normal maximum CRP for that laboratory (i.e., based on the reference standard for that laboratory). Physicians typically order CRP tests from local laboratories, and local laboratories use the rules for calculating normal CRP (i.e., according to their reference standards) in a particular laboratory to determine CRP or hsCRP values and report normal or abnormal (low or high) CRP. Thus, it can be determined by the local laboratory performing the test whether the patient's C-reactive protein (hscRP) level is higher than normal.
The invention shows for the first time in the clinical environment within the range of experimental doses that cana-geminumab can effectively reduce the risk of total lung cancer and fatal lung cancer. The effect was most pronounced in the cohort assigned to the highest canarginoumab dose (300mg, twice a week, then once every 3 months).
Furthermore, the present invention demonstrates for the first time in a clinical setting that an IL-1 β antibody, canargiunumab, can effectively reduce hsCRP levels, and that the reduction of hsCRP is associated with an effect of treating and/or preventing lung cancer, it is therefore possible that an IL-1 β antibody or fragment thereof, such as canargiunumab or gavagunzumab, is effective in treating and/or preventing other cancers that have at least a partial basis for inflammation in a patient, particularly when the patient has a higher than normal level of hsCRP.
Furthermore, the invention provides an effective dose range in which HsCRP levels can be reduced to a threshold below which more cancer patients with at least a partial basis for inflammation can become responders, or below which the same patient can benefit more from the huge therapeutic effect of the drug of the invention with negligible or tolerable side effects.
In one embodiment, the invention provides the use of an IL-1 β binding antibody or a functional fragment thereof (suitably canargizumab or gavaglizumab) for the treatment and/or prevention of cancer (e.g., a cancer with at least a partial basis of inflammation, including but not limited to lung cancer) in a patient, preferably having a high sensitivity C-reactive protein (hsrp) level equal to or greater than 2mg/L, equal to or greater than 3mg/L, equal to or greater than 4mg/L, equal to or greater than 5mg/L, equal to or greater than 6mg/L, equal to or greater than 7mg/L, equal to or greater than 8mg/L, equal to or greater than 9mg/L, equal to or greater than 10mg/L, equal to or greater than 12mg/L, equal to or greater than 15mg/L, equal to or greater than 20mg/L or equal to or greater than 25mg/L, preferably in another embodiment, the patient has a high crp level equal to or greater than 6mg/L, preferably the patient has a high crp level of crp in the first administration of the patient, preferably the patient has a high sensitivity C-reactive protein (crp) level equal to or a crp).
In one embodiment, the invention provides the use of an IL-1 β binding antibody or functional fragment thereof (suitably Canaginumunumab or Gevogelizumab) for the treatment of cancer (e.g. a cancer with at least partial basis of inflammation) in a patient, preferably having a high sensitivity C-reactive protein (hsCRP) level equal to or higher than 2mg/L, higher than 6mg/L, equal to or higher than 10mg/L, or equal to or higher than 20mg/L prior to the first administration of a medicament of the invention.
In one embodiment, the invention provides the use of an IL-1 β binding antibody or functional fragment thereof (suitably canargizumab or gavaglizumab) for the treatment of CRC in a patient, preferably having a high sensitivity C-reactive protein (hsCRP) level of equal to or greater than 2mg/L, greater than 6mg/L, equal to or greater than 10mg/L, or equal to or greater than 20mg/L prior to the first administration of a medicament of the invention.
In one embodiment, the invention provides the use of an IL-1 β binding antibody or functional fragment thereof (suitably canargizumab or gavaglizumab) for the treatment of RCC in a patient, preferably having a high sensitivity C-reactive protein (hsCRP) level of equal to or greater than 2mg/L, greater than 6mg/L, equal to or greater than 10mg/L, or equal to or greater than 20mg/L prior to the first administration of a medicament of the invention.
In one embodiment, the invention provides the use of an IL-1 β binding antibody or functional fragment thereof (suitably canargizumab or gavaglizumab) for the treatment of pancreatic cancer in a patient, preferably having a high sensitivity C-reactive protein (hsCRP) level of equal to or greater than 2mg/L, greater than 6mg/L, equal to or greater than 10mg/L, or equal to or greater than 20mg/L prior to the first administration of a medicament of the invention.
In one embodiment, the invention provides the use of an IL-1 β binding antibody or functional fragment thereof (suitably canargizumab or gavaglizumab) for the treatment of melanoma in a patient, preferably having a high sensitivity C-reactive protein (hsCRP) level of equal to or greater than 2mg/L, greater than 6mg/L, equal to or greater than 10mg/L, or equal to or greater than 20mg/L prior to the first administration of a medicament of the invention.
In one embodiment, the invention provides a use of an IL-1 β binding antibody or functional fragment thereof (suitably canargizumab or gavaglizumab) for treating HCC in a patient, preferably having a high sensitivity C-reactive protein (hsCRP) level of equal to or greater than 2mg/L, greater than 6mg/L, equal to or greater than 10mg/L, or equal to or greater than 20mg/L prior to first administration of a medicament of the invention.
In one embodiment, the invention provides the use of an IL-1 β binding antibody or functional fragment thereof (suitably canargizumab or gavaglizumab) for the treatment of gastric cancer (including esophageal cancer) in a patient, preferably having a high sensitivity C-reactive protein (hsCRP) level of equal to or greater than 2mg/L, greater than 6mg/L, equal to or greater than 10mg/L, or equal to or greater than 20mg/L prior to the first administration of a medicament of the invention.
In one embodiment, the invention provides a use of an IL-1 β binding antibody or functional fragment thereof (suitably canajirimumab) in the treatment and/or prevention of lung cancer in a patient, wherein said patient has atherosclerosis.
In one embodiment, the invention provides for the use of canargiunumab in the treatment and/or prevention of lung cancer in a patient, wherein said patient is eligible for a CV event.
As used herein, the term "eligible CV event" is selected from the group consisting of Myocardial Infarction (MI), stroke, unstable angina, revascularization, stent thrombosis, acute coronary syndrome, or any other CV event (excluding cardiovascular death) prior to initiation of treatment with IL-1 β binding antibody or functional fragment thereof.
In one embodiment, the invention provides a method of treating and/or preventing lung cancer in a patient, wherein the patient has previously suffered a myocardial infarction. In another embodiment, the patient is a stable post-myocardial infarction patient.
As used herein, IL-1 β inhibitors include, but are not limited to, Cainajirimumab or a functional fragment thereof, Gevojizumab or a functional fragment thereof, anakinra, diacerein, linacecept, IL-1 affibody (SOBI 006, Z-FC (Orphan Biovitrum/affibody, Sweden) and Lujizumab (ABT-981) (Yapek corporation), CDP-484 (cell technology corporation (Celltech)), LY-2189102 (Li Laiyi corporation (Lilly)).
In one embodiment of any of the uses or methods of the invention, the IL-1 β binding antibody is Canagagenuzumab (ACZ885) is a high affinity, fully human IgG1/k monoclonal antibody to interleukin-1 β, developed for the treatment of IL-1 β driven inflammatory diseases.
In other embodiments of any of the uses or methods of the invention, the IL-1 β binding antibody is gavoglizumab (XOMA-052), a high affinity, humanized IgG2 isotype monoclonal antibody to interleukin-1 β, developed for the treatment of IL-1 β driven inflammatory diseases.
In one embodiment, the IL-1 β binding antibody is LY-2189102, which is a humanized interleukin-1 β (IL-1 β) monoclonal antibody.
In one embodiment, the IL-1 β -binding antibody or functional fragment thereof is CDP-484 (cell technology corporation), an antibody fragment that blocks IL-1 β.
In one embodiment, the IL-1 β binding antibody or functional fragment thereof is an IL-1 affibody (SOBI 006, Z-FC (Orphan Biovitrrum/affibody, Sweden)).
The present invention demonstrates for the first time in a clinical setting that an IL-1 β antibody, canarginoumab, is effective at reducing hsCRP levels, and that the reduction in hsCRP is associated with an effect of treating and/or preventing lung cancer if an IL-1 β inhibitor (e.g., an IL-1 β antibody or a functional fragment thereof) is administered in a dosage range effective to reduce hsCRP levels in a patient having a cancer with at least a partial basis for inflammation, the therapeutic effect of the cancer may be achieved.
Thus, in one embodiment the invention comprises administering IL-1 β binding antibody or functional fragment thereof to a patient suffering from a cancer with at least a partial basis of inflammation, including but not limited to lung cancer, within a range of about 30mg to about 750mg per treatment, preferably within a range of about 60mg to about 400mg per treatment, alternatively 100mg-600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg per treatment, preferably 150mg to 300mg per treatment, alternatively about 90mg to about 300mg, or about 90mg to about 200mg per treatment, alternatively at least 150mg, at least 180mg, at least 300mg per treatment, at least 250mg per treatment, 150mg to 300mg per treatment, in one embodiment, a patient suffering from a cancer with at least a partial basis of inflammation (including lung cancer) is treated every 2 weeks, three weeks, four weeks (monthly), 6 weeks, two months (every 2 months) or a quarterly (every 3 months) of the treatment, the patients receiving a cancer, especially a renal carcinoma, preferably a lung cancer, a cancer, preferably a lung cancer, a cancer.
In a preferred embodiment, a patient with a cancer having at least a partial basis of inflammation (including, but not limited to, lung cancer) receives a dose of IL-1 β binding antibody or functional fragment thereof of about 90mg to about 450mg per treatment.
In one embodiment, the cancer having at least a partial basis for inflammation is breast cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is RCC. In one embodiment, the cancer is melanoma. In one embodiment, the cancer is pancreatic cancer.
In practice, the time interval sometimes cannot be strictly maintained due to limitations in the availability of the doctor, patient or medication/facility. Thus, the time interval may vary slightly, typically between ± 5 days, ± 4 days, ± 3 days, ± 2 days or preferably ± 1 day.
In one embodiment, the invention comprises administering an IL-1 β binding antibody or functional fragment thereof to a patient having a cancer with at least a partial basis of inflammation (including but not limited to lung cancer) at a total dose of 100mg to 750mg, alternatively 100mg-600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg, alternatively at a total dose of at least 150mg, at least 180mg, at least 250mg, at least 300mg, over a period of 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks, preferably 4 weeks.
In one embodiment, the total dose of the medicament of the invention is administered a plurality of times, preferably 2,3 or 4 times, over the period defined above. In one embodiment, the medicament of the invention is administered once within the above defined period.
Self-induction of IL-1 β has been shown in vitro in human mononuclear blood, human vascular endothelial and vascular smooth muscle cells, and in rabbits, where IL-1 has been shown to induce its own gene expression and circulating IL-1 β levels (Dinarello et al, 1987, Warner et al, 1987a, and Warner et al, 1987 b).
This induction period of more than two weeks by administration of the first dose followed by administration of the second dose two weeks after the first dose administration is to ensure that self-induction of the IL-1 β pathway is adequately inhibited at the start of treatment this early high dose administration, complete inhibition of IL-1 β -related gene expression, coupled with sustained canarginous mab therapeutic effect (which has been demonstrated to last the entire quaternary dosing cycle of CANTOS), is to minimize the likelihood of IL-1 β rebound.
Thus, in one embodiment, the present invention specifically contemplates a second administration of the drug of the present invention up to two weeks, preferably two weeks, from the first administration, while maintaining the above dosing schedule. Then, the third and subsequent administrations will follow a schedule of every 2 weeks, every 3 weeks, every 4 weeks (monthly), every 6 weeks, every two months (every 2 months), or every quarter (every 3 months).
In one embodiment, the IL-1 β binding antibody is a canargiunumab, wherein the canargiunumab is administered to a patient having a cancer with at least a partial basis of inflammation (including lung cancer), each treatment ranging from about 100mg to about 750mg, alternatively 100mg-600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg, alternatively about 200mg to 400mg, 200mg to 300mg, alternatively at least 150mg, at least 200mg, at least 250mg, at least 300mg per treatment, in one embodiment, a patient having a cancer with at least a partial basis of inflammation (including lung cancer), in one embodiment, every 2 weeks, every 3 weeks, every 4 weeks (monthly), every 6 weeks, two months (every 2 months), or every 3 months, a safe dose of the canargiunknounknounumab or a dose of at least 200mg to 200mg per month, preferably, when the patient has a partial basis of inflammation (including lung cancer), the patient has a cancer with at least a partial basis of inflammation, preferably a cancer, the patient has a further dose of the cancer that is a lung cancer that is a non-cancer, preferably a non-cancer, a non-cancer with at least a partial basis of cancer, a cancer, preferably a cancer, a cancer with at least a non-based cancer, a non-based cancer, preferably, a non-based cancer.
Suitable dosages and administrations as described above are suitable for use of the functional fragment of canargizumab according to the invention.
In one embodiment, the invention includes administering canarginoumab to a patient having a cancer with at least a partial basis of inflammation (including lung cancer), over a period of 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks, preferably 4 weeks, at a total dose of 100mg to about 750mg, alternatively 100mg-600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg, preferably 300mg to 450 mg; alternatively at least 150mg, at least 200mg, at least 250mg, at least 300mg, preferably at least 300 mg. In one embodiment, the canargiunumab is administered multiple times, preferably 2,3 or 4 times, over the period defined above. In one embodiment, the canarginoumab is administered once over the above-defined time period. In one embodiment, the preferred total dose of canargiunumab is from 200mg to 450mg, further preferred from 300mg to 450mg, further preferred from 350mg to 450 mg.
In one embodiment, the present invention specifically contemplates a second administration of canargizumab up to two weeks, preferably two weeks, from the first administration, while maintaining the above-described dosing schedule.
In one embodiment, the invention includes administering canargiunumab at a dose of 150mg every 2 weeks, every 3 weeks, or monthly.
In one embodiment, the invention includes administering canargimumab at a dose of 300mg every 2 weeks, every 3 weeks, monthly, every 6 weeks, every two months (every 2 months), or every quarter (every 3 months).
In one embodiment, the invention includes administering canargizumab once per month (monthly) at a dose of 300 mg. In another embodiment, the present invention specifically contemplates a second administration of canargizumab at a dose of 300mg up to two weeks, preferably two weeks, from the first administration while maintaining the above dosing schedule.
In one embodiment of the invention, canargiunumab is administered to a patient in need thereof at a dose of 300mg, twice a week, and then once every 3 months.
In one embodiment, the cancer having at least a partial basis for inflammation is breast cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is renal cancer. In one embodiment, the cancer is melanoma.
In one embodiment, the invention includes administering to a patient having a cancer with at least a partial basis of inflammation (including lung cancer) gemtuzumab ozogamicin in a range of about 30mg to about 450mg per treatment, alternatively 90mg-450mg, 90mg to 360mg, 90mg to 270mg, 90mg to 180mg per treatment; alternatively 120mg-450mg, 120 mg-360 mg, 120 mg-270 mg, 120mg-180mg per treatment, alternatively 150mg-450mg, 150 mg-360 mg, 150 mg-270 mg, 150 mg-180mg per treatment, alternatively 180mg-450mg, 180 mg-360 mg, 180 mg-270 mg per treatment; alternatively, from about 60mg to about 360mg, from about 60mg to 180mg per treatment; alternatively at least 150mg, at least 180mg, at least 240mg, at least 270mg per treatment. In one embodiment, patients with cancers that have at least a partial basis for inflammation, including lung cancer, receive treatment every 2 weeks, every 3 weeks, monthly (every 4 weeks), every 6 weeks, every two months (every 2 months), or quarterly (every 3 months). In one embodiment, a patient with a cancer having at least a partial basis of inflammation (including lung cancer) receives at least one treatment, preferably one treatment, monthly. Cancers that typically have at least a partial basis for inflammation include, but are not limited to, lung cancer, particularly NSCLC, colorectal cancer, melanoma, gastric cancer (including esophageal cancer), Renal Cell Carcinoma (RCC), breast cancer, hepatocellular carcinoma (HCC), prostate cancer, bladder cancer, AML, multiple myeloma, and pancreatic cancer. In one embodiment, the preferred range of gemfibrozumab is 150mg to 270 mg. In one embodiment, the preferred range of gavoglizumab is 60mg to 180mg, further preferred 60mg to 90 mg. In one embodiment, the preferred range of gemfibrozumab is 90mg to 270mg, further preferred 90mg to 180 mg. In one embodiment, the preferred schedule is every 3 weeks or every month. In one embodiment, the patient receives between 60mg and 90mg of gemfibrozumab every 3 weeks. In one embodiment, the patient receives between 60mg and 90mg of gemfibrozumab monthly. In one embodiment, a patient having a cancer with at least a partial basis of inflammation receives about 90mg to about 360mg, 90mg to about 270mg, 120mg to 270mg, 90mg to 180mg, 120mg, or 90mg of gavagizumab every 3 weeks. In one embodiment, a patient having a cancer with at least a partial basis of inflammation receives from about 90mg to about 360mg, 90mg to about 270mg, 120mg to 270mg, 90mg to 180mg, 120mg, or 90mg of gemfibrozumab per month.
In one embodiment, a patient with a cancer having at least a partial basis of inflammation receives about 120mg of gemfibrozumab every 3 weeks. In one embodiment, the patient receives about 120mg of gemfibrozumab monthly. In one embodiment, a patient with a cancer having at least a partial basis of inflammation receives about 90mg of gemfibrozumab every 3 weeks. In one embodiment, the patient receives about 90mg of gemfibrozumab monthly. In one embodiment, a patient with a cancer having at least a partial basis of inflammation receives about 180mg of gemfibrozumab every 3 weeks. In one embodiment, the patient receives about 180mg of gemfibrozumab monthly. In one embodiment, a patient with a cancer having at least a partial basis of inflammation receives about 200mg of gemfibrozumab every 3 weeks. In one embodiment, the patient receives about 200mg of gemfibrozumab monthly.
When safety concerns arise, the dose may be titrated down, preferably by increasing the dosing interval, preferably by doubling the dosing interval. For example, a regimen of 120mg per month or every 3 weeks may be changed to every two months or every 6 weeks, respectively. In an alternative embodiment, a patient with a cancer with at least a partial basis for inflammation receives a dose of 120mg of gemfibrozumab every two months or every six weeks during the titration reduction phase or maintenance phase or throughout the treatment phase independent of any safety issues.
In one embodiment, the gemfibrozumab or functional fragment thereof is administered intravenously. In one embodiment, the gemfibrozumab is administered subcutaneously.
In one embodiment, the gavojizumab is administered 20-120mg, preferably 30-60mg, 30-90mg, 60-90mg, preferably intravenously, preferably every 3 weeks. In one embodiment, the gavojizumab is administered 20-120mg, preferably 30-60mg, 30-90mg, 60-90mg, preferably intravenously, preferably every 4 weeks. In one embodiment, the gavojizumab is administered 30-180mg, preferably 30-60mg, 30-90mg or 60-90mg, 90-120mg, preferably subcutaneously, preferably every 3 weeks. In one embodiment, gavojizumab is administered 30-180mg, preferably 30-60mg, 30-90mg or 60-90mg, 90-120mg, 120mg-180mg, preferably subcutaneously, preferably every 4 weeks. The dosing regimens disclosed herein are applicable to each of the embodiments disclosed herein relating to gemfibrozumab, including but not limited to monotherapy or in combination with one or more chemotherapeutic agents, different cancer indications, e.g., lung cancer, RCC, CRC, gastric cancer, melanoma, breast cancer, pancreatic cancer, for use in the adjuvant setting or in first, second or third line therapy.
Suitable dosages and administrations as described above are suitable for use of the functional fragments of gemtuzumab ozogamicin according to the invention.
In one embodiment, the invention comprises administering to a patient having lung cancer, gavagizumab, at a total dose of 90mg-450mg, 90mg to 360mg, 90mg to 270mg, 90mg to 180mg, alternatively 120mg-450mg, 120mg to 360mg, 120mg to 270mg, alternatively 150mg to 450mg, 150mg to 360mg, 150mg to 270mg, 150mg to 180mg, alternatively 180mg-450mg, 180mg to 360mg, 180mg to 270mg, alternatively at least 90mg, at least 120mg, at least 150mg, at least 180mg over a period of 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks, preferably 4 weeks. In one embodiment, the gemtuzumab ozogamicin is administered multiple times, preferably 2,3 or 4 times, over the period defined above. In one embodiment, gemfibrozumab is administered once over the above defined period of time. In one embodiment, the preferred total dose of gemfibrozumab is 180mg to 360 mg. In one embodiment, a patient with lung cancer is treated with gevorbizumab at least once, preferably once, per month.
In one embodiment, the present invention specifically contemplates a second administration of gemfibrozumab up to two weeks, preferably two weeks, from the first administration, while maintaining the above-described dosing schedule.
In one embodiment, the invention includes administering gevoglizumab at a dose of 60mg every 2 weeks, every 3 weeks, or monthly.
In one embodiment, the invention includes administering gevoglizumab at a dose of 90mg every 2 weeks, every 3 weeks, or monthly.
In one embodiment, the invention includes administering gemfibrozumab at a dose of 180mg every 2 weeks, every 3 weeks (± 3 days), monthly, every 6 weeks, every two months (every 2 months), or quarterly (every 3 months).
In one embodiment, the invention includes administering gevoglizumab at a dose of 180mg once a month (monthly). In another embodiment, the present invention contemplates a second administration of gemfibrozumab at a dose of 180mg up to two weeks, preferably two weeks, from the first administration, while maintaining the above dosing schedule.
In one embodiment, the cancer having at least a partial basis for inflammation is breast cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is renal cancer. In one embodiment, the cancer is melanoma.
In one embodiment, the invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably canargiunumab, for use in the treatment and/or prevention of cancer having at least a partial basis of inflammation, including lung cancer, wherein the risk of cancer having at least a partial basis of inflammation (including lung cancer) is reduced by at least 30%, at least 40%, at least 50% at 3 months after first administration compared to an untreated patient in a preferred embodiment, the first administered dose is 300mg in another preferred embodiment, the first administered dose is 300mg followed by a second administration of 300mg within two weeks, preferably the result is achieved by administering a 200mg dose of canargiunumab every 3 weeks.
In one embodiment, the invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably canaryitumumab, for use in the treatment and/or prevention of cancers with at least a partial basis of inflammation, including lung cancer, wherein the risk of lung cancer death is reduced by at least 30%, at least 40% or at least 50% compared to untreated patients preferably said result is achieved by administering a dose of 200mg of canaryitumumab every 3 weeks or a dose of 300mg of canaryitumumab every month, preferably for at least one year, preferably for up to 3 years.
In one embodiment, the invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably canaryitumumab, for use in the treatment and/or prevention of lung cancer, wherein the incidence of adenocarcinoma or poorly differentiated large cell carcinoma is reduced by at least 30%, at least 40% or at least 50% compared to a patient not receiving such treatment, preferably said result is achieved by administering a 300mg dose of canaryitumumab per month or preferably a 200mg dose of canaryitumumab every 3 weeks or month, preferably for at least one year, preferably for up to 3 years.
In one embodiment, the present invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably canargiunumab, for use in the treatment and/or prevention of cancer, wherein the risk of total cancer death is reduced by at least 30%, at least 40% or at least 50% compared to a patient not receiving such treatment, preferably said result is achieved by administering a 300mg or 200mg dose of canargiunumab monthly, or preferably a 200mg dose of canargiunumab every 3 weeks, preferably subcutaneously, preferably for at least one year, preferably up to 3 years.
In one embodiment, the present invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably canargizumab or a functional fragment thereof, suitably gavojizumab or a functional fragment thereof, for use in the treatment of a cancer with at least a partial basis for inflammation, wherein the risk of cancer death is reduced by at least 30%, at least 40% or at least 50% compared to a patient not receiving treatment, preferably the result is achieved by administering a 200mg dose of canargizumab every 3 weeks or month, preferably for at least one year, preferably for up to 3 years.
In one embodiment, the invention provides canarginoumab for treating and/or preventing lung cancer, wherein the effect is dose-dependent with a 67% and 77% reduction in the relative risk of total and fatal lung cancer, respectively, in patients randomly assigned to the highest canarginoumab dose (300mg, twice within two weeks, then once every 3 months).
In one embodiment, the present invention provides canargiunumab for use in the treatment and/or prevention of lung cancer, wherein a beneficial effect of canargiunumab on sporadic lung cancer is observed within weeks after the first administration. In a preferred embodiment, the first administered dose is 300 mg. In another preferred embodiment, the dose administered for the first time is 300mg, followed by a second administration of 300mg within two weeks. In another preferred embodiment, a 200mg dose of canargiunumab is administered every three weeks or every month.
In one aspect, the invention provides an IL-1 β binding antibody or a functional fragment thereof for use in the treatment of cancer, such as cancer with at least a partial basis for inflammation, including but not limited to lung cancer, in particular NSCLC, wherein the efficacy of the treatment is related to a reduction of hsCRP in the patient compared to a prior treatment in one embodiment, the invention provides an IL-1 β binding antibody or a functional fragment thereof for use in the treatment of cancer, such as cancer with at least a partial basis for inflammation, including but not limited to lung cancer, in particular NSCLC, in a patient whose level, more precisely hsCRP level, is reduced to below 15mg/L, below 10mg/L, preferably to below 6mg/L, preferably to below 4mg/L, preferably to below 3mg/L, preferably to below 2.3mg/L, preferably to below 2mg/L, preferably to below 8mg/L, hepatocellular carcinoma, including at least partial myeloma, pancreatic carcinoma (including breast cancer, renal cell carcinoma, colorectal cancer, pancreatic carcinoma, particularly lung carcinoma, colorectal carcinoma, including breast cancer, renal carcinoma, colorectal carcinoma, and colorectal carcinoma).
In one preferred embodiment, the suitable dose of the first administration of the canarginoumab is 300mg per month in one preferred embodiment, another dose is administered 2 weeks apart from the first administration.
In one embodiment, the IL-1 β binding antibody is gavoglizumab or a functional fragment thereof in a preferred embodiment, a suitable dose of the first administration of gavoglizumab is 180mg in a preferred embodiment, gavoglizumab is administered at a dose of 60mg to 90mg every 3 weeks or every month in a preferred embodiment, gavoglizumab is administered at a dose of 120mg every 3 weeks or every 4 weeks (monthly) in a preferred embodiment, gavoglizumab is administered intravenously in a preferred embodiment, gavoglizumab is administered at a dose of 90mg every 3 weeks or every 4 weeks (monthly) in a preferred embodiment, a patient with a cancer that has at least a partial basis of inflammation receives about 120mg of gavoglizumab every 3 weeks in an embodiment, a patient with a cancer that has at least a partial basis of inflammation receives about 180mg of gavoglizumab in an embodiment, a patient with an inflammation receives about 180mg of gavoglizumab per month in an embodiment, said patient has a subcutaneous administration of about 180mg of gavoglizumab.
Further preferably, after the first administration of the medicament of the invention according to the dosage regimen of the invention, the hsCRP level of the patient is reduced to below 10mg/L, preferably to below 6mg/L, preferably to below 4mg/L, preferably to below 3mg/L, preferably to below 2.3mg/L, preferably to below 2mg/L, to below 1.8 mg/L. In a preferred embodiment, a suitable dose for the first administration of canarginoumab is at least 150mg, preferably at least 200 mg. In a preferred embodiment, a suitable dose for the first administration of gemfibrozumab is 90 mg. In a preferred embodiment, a suitable dose for the first administration of gemfibrozumab is 120 mg. In a preferred embodiment, a suitable dose for the first administration of gemfibrozumab is 180 mg. In a preferred embodiment, a suitable dose for the first administration of gemfibrozumab is 200 mg.
In one embodiment, the cancer having at least a partial basis for inflammation is breast cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is renal cancer. In one embodiment, the cancer is melanoma.
In one aspect, the invention provides an IL-1 β binding antibody or a functional fragment thereof (e.g., canargizumab or gavaglizumab) for use in treating cancer (which has at least a partial basis for inflammation, including lung cancer, particularly NSCLC) in a patient, wherein hsCRP levels in the patient are reduced by at least 15%, at least 20%, at least 30%, or at least 40% 6 months or preferably 3 months after the first administration of an appropriate dose (preferably according to a dosing regimen of the invention) of an IL-1 β binding antibody or a functional fragment thereof as compared to hsCRP levels immediately prior to the first administration of an IL-1 β binding antibody or a functional fragment thereof (canargizumab or gavagizumab).
In one aspect, the invention provides an IL-1 β binding antibody or functional fragment thereof (e.g., canargizumab or gavageryzumab) for use in treating cancer (e.g., cancer with at least a partial basis of inflammation, including lung cancer, particularly NSCLC) in a patient, wherein IL-1 β binding antibody or functional fragment thereof (e.g., canargizumab or gavageryzumab) is administered at least 15%, at least 20%, at least 30% or at least 40% about 6 months after the first administration of an appropriate dose (preferably according to the dosing regimen of the invention) as compared to the IL-6 level immediately prior to the first administration, the term "about" as used herein includes a change of 3 months ± 10 days or a change of 6 months ± 15 days, preferably at a dose of one or more than 200mg once per month, preferably one month after the first administration of the antibody or functional fragment thereof, preferably at one dose of 120mg once per month, preferably at one or more than 200mg once per week, preferably at one month after the first administration of the first dose of the antibody or functional fragment thereof (e.90 mg once per month) as compared to the IL-6 level immediately prior to the first administration of the second administration of the first administration.
The reduction in hsCRP levels and the reduction in IL-6 levels can be used alone or in combination to indicate therapeutic efficacy or as a prognostic indicator.
In one embodiment, the cancer having at least a partial basis for inflammation is breast cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is renal cancer. In one embodiment, the cancer is melanoma.
In one aspect, the invention provides an IL-1 β binding antibody or a functional fragment thereof for use in the treatment and/or prevention of cancer (at least part of the basis of inflammation, including lung cancer, particularly NSCLC) in a patient having hypersensitive C-reactive protein (hscRP) of ≧ 2mg/L, wherein the antibody is canargiunumab and the patient has a reduced chance of death from the cancer over a period of at least five years.
In one preferred embodiment, the IL-1 β binding antibody is gavogemumab or a functional fragment thereof is administered at a dose of 30mg to 90mg every three weeks, monthly, 6 weeks, every other month, or quarterly, in one preferred embodiment, every 30mg to 90mg every three weeks, monthly, every 6 months, or every quarterly, in another preferred embodiment, every 120, 60, or 120, preferably every three weeks, monthly, 120, or 60, preferably every three weeks, monthly, 6, or quarterly.
Risk factors include, but are not limited to, age, genetic mutation, smoking, long term exposure to inhalable hazards (e.g., for occupational reasons), and the like.
In one embodiment, the patient is over 60 years old, over 62 years old or over 65 years old or over 70 years old. In one embodiment, the patient is a male. In another embodiment, the patient is a female. In one embodiment, the patient is a smoker, in particular a current smoker. Smokers can be understood as a broader definition than the CANTOS test, i.e. persons who smoke more than 5 cigarettes per day (current smokers) or persons with a history of smoking (past smokers). Typically, the history of smoking is over 5 years or over 10 years. Typically, during smoking, 10 or more than 20 cigarettes are smoked per day.
In one embodiment, the patient has been exposed to or is being exposed to long-term exposure (for more than 5 years or even more than 10 years), such as due to occupation, external inhalation toxins, such as asbestos, silica, tobacco, and other external inhalation toxins, if the patient has one of the above, or a combination of any two, any three, any four, any five, or any six of the above conditions, the patient is more likely to develop lung cancer.
In one embodiment, the invention provides an IL-1 β binding antibody or a functional fragment thereof (suitably canargizumab or a functional fragment thereof, or gavage zumab or a functional fragment thereof) for preventing lung cancer in a patient who assesses a high sensitivity C-reactive protein (crp) having equal to or greater than 2mg/L, or equal to or greater than 3mg/L, or equal to or greater than 4mg/L, or equal to or greater than 5mg/L, equal to or greater than 6mg/L, equal to or greater than 8mg/L, equal to or greater than 9mg/L, or equal to or greater than 10mg/L prior to administration of an IL-1 β binding antibody or a functional fragment thereof in a preferred embodiment, the subject assesses a crp level having equal to or greater than 6mg/L prior to administration of an IL-1 β binding antibody or a functional fragment thereof in a preferred embodiment, the subject assesses a crp level having equal to or greater than 10mg/L prior to administration of an IL-1 antibody or a functional fragment thereof in another preferred embodiment, the subject assesses a smoker, or a functional fragment thereof in another embodiment, the subject is a smoker.
In one embodiment, the canargizumab is administered at a dose of 50mg-300mg, 50-150mg, 75mg-150mg, 100mg-150mg, 50mg, 150mg, 200mg, 400mg, or 300mg every 3 months. In a prophylactic aspect, canargizumab is administered to a patient in need thereof at a dose of 50mg, 150mg, or 300mg, preferably 150mg, monthly, every two months, or every three months. In one embodiment, the canargiunumab is administered to a patient in need thereof at a dose of 150mg, 200mg, 400mg, or 300mg every 3 months to prevent lung cancer.
In one embodiment, the gavaglus mab is administered at a dose of 30mg-180mg, 30mg-120mg, 30mg-90mg, 60mg-120mg, 60mg-90mg, 30mg, 60mg, 90mg, or 180mg every 3 months.
In one embodiment, the invention provides an IL-1 β binding antibody or a functional fragment thereof (suitably canargizumab or a functional fragment thereof, or gavaglizumab or a functional fragment thereof) for use in preventing recurrence or relapse of cancer (e.g., a cancer with at least a partial basis of inflammation, including but not limited to lung cancer) in a subject, wherein the subject has cancer or lung cancer that has been removed by surgery (resection-type "adjuvant chemotherapy"). typically a cancer with at least a partial basis of inflammation includes, but is not limited to, lung cancer, particularly NSCLC, colorectal cancer, melanoma, gastric cancer (including esophageal cancer), Renal Cell Carcinoma (RCC), breast cancer, hepatocellular carcinoma (HCC), prostate cancer, bladder cancer, and pancreatic cancer. in a preferred embodiment, the patient has completed post-operative standard chemotherapy (in addition to treatment with the drug of the invention) treatment (typically as standard adjuvant chemotherapy) and/or completed standard post-operative standard chemotherapy includes standard small molecule chemotherapeutic agents and/or antibodies, particularly checkpoint inhibitors in another preferred embodiment, the term post-operative standard chemotherapy includes, small molecule chemotherapeutic agents and/or antibodies, particularly checkpoint inhibitors, particularly gavaglizumab, preferably as a single or as a monthly chemotherapeutic, preferably as a single, when administered in combination with a single, monthly, preferably a monthly, preferably a monthly-120 mg, or monthly-180 mg, preferably a monthly, preferably a monthly-120 mg, or monthly, preferably a monthly, preferably a monthly, or monthly, preferably a monthly, preferably a monthly, or monthly, preferably a monthly, or weekly, a monthly, preferably a monthly, administration of a combination of a standard, preferably a chemotherapeutic, preferably a chemotherapeutic, or a chemotherapeutic, preferably a chemotherapeutic, or a chemotherapeutic, preferably a chemotherapeutic, preferably a non-180, preferably a chemotherapeutic, a chemotherapeutic, preferably a non-180, preferably a chemotherapeutic.
In one embodiment, the cancer having at least a partial basis for inflammation is breast cancer.
In one embodiment, the IL-1 β binding antibody or functional fragment thereof (suitably Canatkinumab or Gevojizumab) is administered to the patient with the cancer having at least a partial basis of inflammation prior to surgery (neoadjuvant chemotherapy) or after surgery (adjuvant chemotherapy). In one embodiment, the IL-1 β binding antibody or functional fragment thereof is administered to the patient prior to, concurrently with, or after radiation therapy.
In one embodiment, the present invention provides canargiunumab or gavagizumab for use as an adjuvant therapy in a NSCLC patient, wherein preferably the patient has complete resection of cancer at stages IIA, IIB, IIIA and IIIB (T >5cm N2) (R0, i.e. negative margin at the time of pathology). In one embodiment, 200mg of canargizumab is administered every 3 weeks or every 4 weeks. In one embodiment, the canargizumab or gavojizumab is administered for at least 6 months, or up to one year, or at least 12 months, preferably one year, preferably subcutaneously. In one embodiment, the canargizumab or gemtuzumab is administered after the patient has completed standard-of-care adjuvant therapy for their NSCLC, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). In one embodiment, the canargizumab or gavagizumab is used as a monotherapy in adjuvant therapy. In one embodiment, the canargizumab or gavaglizumab is used in combination with one or more chemotherapeutic agents in an adjuvant therapy. In one embodiment, the NSCLC is squamous NSCLC. In one embodiment, the NSCLC is non-squamous NSCLC. In one embodiment, the disease-free survival (DFS, i.e., time from the date of randomization to the date of first recorded disease recurrence) of the patient group treated with canarginoumab is at least 2 months, at least 3 months, at least 4 months longer than that of the placebo group (where the patient did not receive canarginoumab). In one embodiment, the relative risk of the group of patients treated with canarginoumab is reduced by 90% or less, preferably 80% or less, compared to the placebo group (where the patients did not receive canarginoumab).
In one aspect, the invention provides an IL-1 β binding antibody or functional fragment thereof (suitably canargizumab or a functional fragment thereof, or gavaglizumab or a functional fragment thereof) for use in treating cancer, particularly cancer with at least a partial basis for inflammation, in a patient in need thereof, wherein the IL-1 β binding antibody or functional fragment thereof is in combination with one or more therapeutic agents (e.g., a chemotherapeutic agent).
Without being bound by theory, it is believed that a typical cancer development requires two steps.first, genetic alterations lead to cell growth and proliferation that are no longer regulated.second, aberrant tumor cells evade surveillance by the immune system.inflammation plays an important role in the second step.thus, controlling inflammation can halt the development of cancer at an early or earlier stage, as supported for the first time by clinical data from the CANTOS test.
Therefore, the addition of an IL-1 β inhibitor, specifically an IL-1 β binding antibody or functional fragment thereof, to standard checkpoint inhibitor therapy will further activate the immune response, particularly in the tumor microenvironment.
In one embodiment, the one or more therapeutic agents is nivolumab.
In one embodiment, the one or more therapeutic agents is lanolizumab.
In one embodiment, the one or more therapeutic agents (e.g., chemotherapeutic agents) are nivolumab and epirubizumab.
In one embodiment, the one or more chemotherapeutic agents is cabozantinib or a pharmaceutically acceptable salt thereof.
In one embodiment, the one or more therapeutic agents (e.g., chemotherapeutic agents) is altritlizumab plus bevacizumab.
In one embodiment, the one or more chemotherapeutic agents is bevacizumab.
In one embodiment, the one or more chemotherapeutic agents is FOLFIRI, FOLFOX, or XELOX.
In one embodiment, the one or more chemotherapeutic agents is FOLFIRI plus bevacizumab or FOLFOX plus bevacizumab.
In one embodiment, the one or more chemotherapeutic agents is platinum-based duplex chemotherapy (PT-DC).
Chemotherapeutic agents are cytotoxic and/or cytostatic drugs (drugs that kill malignant cells or inhibit their proliferation, respectively) as well as checkpoint inhibitors. The chemotherapeutic agent may be, for example, a small molecule agent, a biological agent (e.g., antibodies, cells and gene therapy, cancer vaccines), a hormone, or other natural or synthetic peptides or polypeptides. Well-known chemotherapeutic agents include, but are not limited to, platinum agents (e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin, lipoplatin, satraplatin, picoplatin), antimetabolites (e.g., methotrexate, 5-fluorouracil, gemcitabine, pemetrexed, mitotic inhibitors (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel, taxotere, docetaxel), alkylating agents (e.g., cyclophosphamide, chloroethylamine hydrochloride, ifosfamide, melphalan, tiatipar), vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinorelbine), topoisomerase inhibitors (e.g., etoposide, teniposide, topotecan, irinotecan, camptothecin, doxorubicin), antitumor antibiotics (e.g., mitomycin C) and/or hormone modulators (e.g., anastrozole, tamoxifen).
In one embodiment, a preferred combination partner for an IL-1 β binding antibody or functional fragment thereof (e.g., Cajanus geminizumab or Gevojizumab) is a mitotic inhibitor, preferably docetaxel.
In one embodiment, the preferred combination partner for IL-1 β binding antibodies or functional fragments thereof (e.g., Canaguizumab or Gerojizumab) is a platinum agent, preferably cisplatin.
Chemotherapy may include administration of a single anti-cancer agent (drug) or administration of a combination of anti-cancer agents (drugs), for example, one of the following, typically a combination of the following: carboplatin and taconazole (taxol); gemcitabine and cisplatin; gemcitabine and vinorelbine; gemcitabine and paclitaxel; cisplatin and vinorelbine; cisplatin and gemcitabine; cisplatin and paclitaxel (Taxol); cisplatin and docetaxel (Taxotere); cisplatin and etoposide; cisplatin and pemetrexed; carboplatin and vinorelbine; carboplatin and gemcitabine; carboplatin and paclitaxel (Taxol); carboplatin and docetaxel (Taxotere); carboplatin and etoposide; carboplatin and pemetrexed. In one embodiment, the one or more chemotherapeutic agents is platinum-based duplex chemotherapy (PT-DC).
Another class of chemotherapeutic agents are inhibitors, especially tyrosine kinase inhibitors, which specifically target growth promoting receptors, especially VEGF-R, EGFR, PFGF-R and ALK or downstream members of their signal transduction pathways, whose mutation or overproduction leads to or contributes to the carcinogenesis of tumors at that site (targeted therapy). Examples of targeted therapeutic drugs approved by the U.S. Food and Drug Administration (FDA) for targeted therapy of lung cancer include, but are not limited to, bevacizumab
In one embodiment, the chemotherapeutic agent or agents to be combined with the IL-1 β binding antibody or fragment thereof (suitably canargizumab or gevigizumab) are agents that are standard-of-care agents for lung cancer, including NSCLC and SCLC the standard-of-care can be found, for example, from adjunctive chemotherapy and adjunctive radiotherapy in the American Society for Clinical Oncology (ASCO) guidelines for the systemic treatment of patients with stage IV non-small cell lung cancer (NSCLC) or in the American Society for Clinical Oncology (ASCO) guidelines for stage I-IIIA resectable non-small cell lung cancer.
In one embodiment, the chemotherapeutic agent or agents to be combined with the IL-1 β binding antibody or fragment thereof (suitably canargizumab or gavaglizumab) is a platinum-containing agent or a platinum-based duplex chemotherapy (PT-DC).
In one embodiment, one or more therapeutic agent to be combined with an IL-1 β binding antibody or fragment thereof (suitably canargizumab or gavaglizumab) is a checkpoint inhibitor in another embodiment, the checkpoint inhibitor is nivolumab in another embodiment, the checkpoint inhibitor is lanolinzumab in another embodiment, the checkpoint inhibitor is altlizumab in another embodiment, the checkpoint inhibitor is PDR-001 (spartalizumab) in another embodiment, the checkpoint inhibitor is durvazumab (durvalumab) in one embodiment, the checkpoint inhibitor is avelumab (avelumab) in immunotherapy against immune checkpoints, also known as checkpoint inhibitors, currently becoming a key agent in cancer therapy, the immune inhibitor receptor inhibitor or ligand inhibitor, examples of inhibitory targets include, but are not limited to, co-inhibitory molecules (e.g., PD-1 inhibitors (e.g., anti-PD-1 antibodies), inhibitors of PD-L2 (e.g., anti-PD-L5393), anti-IL-receptor agonist molecules such as anti-IL-receptor agonist antibody (e g., anti-IL-3-IL-receptor antagonist), anti-IL-binding antibody (e.g., anti-IL-binding antibody), anti-IL-binding antibody, e.g., anti-IL-binding antibody, anti-IL-1-IL-binding antibody, anti-binding antibody, e.g., anti-binding antibody, anti.
PD-1 inhibitors
In one aspect of the invention, the inhibitor of IL-1 β or a functional fragment thereof is administered with a PD-1 inhibitor, in one embodiment, the PD-1 inhibitor is selected from PDR001 (Stbadatuzumab) (Nowa), Nwaruzumab (Bethesubes Corp.), Loriluzumab (Merck & Co.), PILITHICUZIMA (CureTech), MEDI0680 (Mediadema Limited, England), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigype), BGB-108 (Baiji state), INCSAHR 1210 (Incyte), or AMPLIM-224 (Amplim).
In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody molecule, as described in US2015/0210769 (which is incorporated by reference in its entirety) published on 30/7/2015 entitled "antibody molecule of PD-1 and uses thereof".
In one embodiment, the anti-PD-1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO 506 and VL comprising the amino acid sequence of SEQ ID NO 520. In one embodiment, the anti-PD-1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO 506 and VL comprising the amino acid sequence of SEQ ID NO 516.
TABLE A amino acid and nucleotide sequences of exemplary anti-PD-1 antibody molecules
In one embodiment, the anti-PD-1 antibody is sibatuzumab.
In one embodiment, the anti-PD-1 antibody is nivolumab.
In one embodiment, the anti-PD-1 antibody molecule is lanolizumab.
In one embodiment, the anti-PD-1 antibody molecule is pidilizumab.
In one embodiment, the anti-PD-1 antibody molecule is MEDI0680 (meidimuir ltd, english), also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US 9,205,148 and WO 2012/145493 (which are incorporated by reference in their entirety). Other exemplary anti-PD-1 molecules include REGN2810 (Producer corporation), PF-06801591 (Perey pharmaceuticals Inc.), BGB-A317/BGB-108 (Baiji State corporation), INCSFR 1210 (Nester corporation), and TSR-042(Tesaro corporation).
Other known anti-PD-1 antibodies include those described, for example, in: WO2015/112800, WO 2016/092419, WO 2015/085847, WO 2014/179664, WO 2014/194302, WO 2014/209804, WO 2015/200119, US 8,735,553, US 7,488,802, US 8,927,697, US 8,993,731, and US 9,102,727 (which are incorporated by reference in their entirety).
In one embodiment, an anti-PD-1 antibody is an antibody that competes with one of the anti-PD-1 antibodies described herein for binding to the same epitope on PD-1 and/or for binding to the same epitope on PD-1.
In one embodiment, the PD-1 inhibitor is a peptide that inhibits the PD-1 signaling pathway, for example as described in US 8,907,053 (which is incorporated by reference in its entirety). In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence)). In one embodiment, the PD-1 inhibitor is AMP-224(B7-DCIg (Amplimmun)), for example, as disclosed in WO 2010/027827 and WO2011/066342, which are incorporated by reference in their entirety.
PD-L1 inhibitors
In one aspect of the invention, the inhibitor of IL-1 β or a functional fragment thereof is administered with an inhibitor of PD-L1 in some embodiments, the PD-L1 inhibitor is selected from FAZ053 (Nowa), Attributab (Gentag/Roche), Avermectin (Merck Serono and Perey pharmaceuticals), Duvaluzumab (England Medizuimsen, Inc./Asricon), or BMS-936559 (Becky Mexican).
In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule, as disclosed in US 2016/0108123 (which is incorporated by reference in its entirety) published on 21/4/2016, entitled "antibody molecule of PD-L1 and uses thereof".
In one embodiment, the anti-PD-L1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO:606 and VL comprising the amino acid sequence of SEQ ID NO: 616. In one embodiment, the anti-PD-L1 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO:620 and VL comprising the amino acid sequence of SEQ ID NO: 624.
Table b. amino acid and nucleotide sequences of exemplary anti-PD-L1 antibody molecules
In one embodiment, the anti-PD-L1 antibody molecule is atelizumab (genet tach/roche), also known as MPDL3280A, RG7446, RO5541267, yw243.55.s70, or TECENTRIQTM. Alemtuzumab and other anti-PD-L1 antibodies are disclosed in US 8,217,149, which are incorporated by reference in their entirety.
In one embodiment, the anti-PD-L1 antibody molecule is avizumab (merck snow lnco and feverfew), also known as MSB 0010718C. Abelmumab and other anti-PD-L1 antibodies are disclosed in WO2013/079174 (which is incorporated by reference in its entirety).
In one embodiment, the anti-PD-L1 antibody molecule is dutvacizumab (engleri meduius ltd/astrikon), also known as MEDI 4736. Duvaluzumab and other anti-PD-L1 antibodies are disclosed in US 8,779,108 (which is incorporated by reference in its entirety).
In one embodiment, the anti-PD-L1 antibody molecule is BMS-936559 (jacobian), also known as MDX-1105 or
Other known anti-PD-L1 antibodies include those described, for example, in: WO 2015/181342, WO2014/100079, WO 2016/000619, WO 2014/022758, WO 2014/055897, WO 2015/061668, WO2013/079174, WO 2012/145493, WO 2015/112805, WO 2015/109124, WO 2015/195163, US 8,168,179, US 8,552,154, US 8,460,927, and US 9,175,082 (which are incorporated by reference in their entirety).
In one embodiment, the anti-PD-1 antibody is an antibody that competes with one of the anti-PD-L1 antibodies described herein for binding to the same epitope on PD-L1 and/or binding to the same epitope on PD-L1.
LAG-3 inhibitors
In some embodiments, the LAG-3 inhibitor is selected from LAG525 (Nowa), BMS-986016 (Bezishi, Pterobao, TSR-033 (Tesaro), IMP731 or GSK2831781, and IMP761 (Prima BioMed)).
In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is an anti-LAG-3 antibody molecule, as disclosed in US 2015/0259420 (incorporated by reference in its entirety) published on
In one embodiment, the anti-LAG-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO. 706 and VL comprising the amino acid sequence of SEQ ID NO. 718. In one embodiment, the anti-LAG-3 antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO:724 and VL comprising the amino acid sequence of SEQ ID NO: 730.
TABLE C amino acid and nucleotide sequences of exemplary anti-LAG-3 antibody molecules
In one embodiment, the anti-LAG-3 antibody molecule is BMS-986016 (behcet masforth, inc.) also known as BMS 986016. BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO 2015/116539 and US 9,505,839 (which are incorporated by reference in their entirety). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of: the CDR sequences (or all CDR sequences in general), the heavy or light chain variable region sequences, or the heavy or light chain sequences of BMS-986016, e.g., as disclosed in table D.
In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK2831781(GSK corporation and pragma biomedical corporation). IMP731 and other anti-LAG-3 antibodies are disclosed in WO 2008/132601 and US 9,244,059 (which are incorporated by reference in their entirety). In one embodiment, the anti-LAG-3 antibody molecule comprises one or more of: the CDR sequences (or overall CDR sequences), the heavy or light chain variable region sequences, or the heavy or light chain sequences of IMP731, for example, as disclosed in table D.
Other known anti-LAG-3 antibodies include those described in, for example, WO 2008/132601, WO2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839 (which are incorporated by reference in their entirety).
In one embodiment, the anti-LAG-3 antibody is an antibody that competes with one of the anti-LAG-3 antibodies described herein for binding to the same epitope on LAG-3 and/or binding to the same epitope on LAG-3.
In one embodiment, the anti-LAG-3 inhibitor is a soluble LAG-3 protein, e.g., IMP321 (procima biomedical corporation), e.g., as disclosed in WO 2009/044273 (which is incorporated by reference in its entirety).
Table d. amino acid sequence of exemplary anti-LAG-3 antibody molecules
TIM-3 inhibitors
In one aspect of the invention, an IL-1 β inhibitor or functional fragment thereof is administered with a TIM-3 inhibitor, hi some embodiments, the TIM-3 inhibitor is MGB453 (Nowa) or TSR-022 (Tasaxole).
In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule, as disclosed in US2015/0218274 published 2015 8/6 (which is incorporated by reference in its entirety) entitled "antibody molecule of TIM-3 and uses thereof".
In one embodiment, the anti-TIM-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO. 806 and a VL comprising the amino acid sequence of SEQ ID NO. 816. In one embodiment, the anti-TIM-3 antibody molecule comprises: a VH comprising the amino acid sequence of SEQ ID NO 822 and a VL comprising the amino acid sequence of SEQ ID NO 826.
The antibody molecules described herein can be made by vectors, host cells, and methods described in US2015/0218274 (which is incorporated by reference in its entirety).
TABLE E amino acid and nucleotide sequences of exemplary anti-TIM-3 antibody molecules
In one embodiment, the anti-TIM-3 antibody molecule is TSR-022 (aneptatys bio/thazaro). In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of TSR-022, the heavy or light chain variable region sequences, or the heavy or light chain sequences. In one embodiment, the anti-TIM-3 antibody molecule comprises one or more of: APE5137, or a CDR sequence (or overall all CDR sequences) of APE5121, a heavy chain or light chain variable region sequence, or a heavy chain or light chain sequence, e.g., as disclosed in table F. APE5137, APE5121 and other anti-TIM-3 antibodies are disclosed in WO 2016/161270 (which is incorporated by reference in its entirety).
In one embodiment, the anti-TIM-3 antibody molecule is antibody clone F38-
Other known anti-TIM-3 antibodies include, for example, those described in WO 2016/111947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087 (which are incorporated by reference in their entirety).
In one embodiment, the anti-TIM-3 antibody is an antibody that competes with one of the anti-TIM-3 antibodies described herein for binding to the same epitope on TIM-3 and/or binding to the same epitope on TIM-3.
TABLE F amino acid sequences of exemplary anti-TIM-3 antibody molecules
GITR agonists
In some embodiments, the GITR agonist is GWN323 (Nowa (NVS)), BMS-986156, MK-4166 or MK-1248 (Merck)), TRX518 (Leap Therapeutics), INCAGN1876 (Nepete/Agenus), AMG 228 (Amersham) or INBRX-110 (Inhibrx).
In one embodiment, the GITR agonist is an anti-GITR antibody molecule. In one embodiment, the GITR agonist is an anti-GITR antibody molecule as described in WO 2016/057846 (incorporated by reference in its entirety) published on
In one embodiment, the anti-GITR antibody molecule comprises: VH comprising the amino acid sequence of SEQ ID NO:901 and VL comprising the amino acid sequence of SEQ ID NO: 902.
Table G: amino acid and nucleotide sequences of exemplary anti-GITR antibody molecules
In one embodiment, the anti-GITR antibody molecule is BMS-986156 (Bristol-Myers Squibb), also known as BMS986156 or BMS 986156. BMS-986156 and other anti-GITR antibodies are disclosed, for example, in US 9,228,016 and WO2016/196792 (which is incorporated by reference in its entirety). In one embodiment, the anti-GITR antibody molecule comprises one or more of: the CDR sequences (or overall all CDR sequences) of BMS-986156, the heavy or light chain variable region sequences, or the heavy or light chain sequences, e.g., as disclosed in table H.
In one embodiment, the anti-GITR antibody molecule is MK-4166 or MK-1248 (Merck). MK-4166, MK-1248, and other anti-GITR antibodies are disclosed in, for example, US 8,709,424, WO 2011/028683, WO 2015/026684, and Mahne et al, Cancer Res [ Cancer research ] 2017; 77(5) 1108-.
In one embodiment, the anti-GITR antibody molecule is TRX518 (lepp therapeutics). TRX518 and other anti-GITR antibodies are disclosed, for example, in US 7,812,135, US 8,388,967, US 9,028,823, WO 2006/105021, and Ponte J et al, (2010) Clinical Immunology; 135: S96, which are incorporated by reference in their entirety.
In one embodiment, the anti-GITR antibody molecule is incag 1876 (genepott/agilaws). INCAGN1876 and other anti-GITR antibodies are disclosed, for example, in US2015/0368349 and WO 2015/184099 (which are incorporated by reference in their entirety).
In one embodiment, the anti-GITR antibody molecule is AMG 228 (america ann company). AMG 228 and other anti-GITR antibodies are disclosed, for example, in US 9,464,139 and WO 2015/031667 (which are incorporated by reference in their entirety).
In one embodiment, the anti-GITR antibody molecule is INBRX-110 (print sier). INBRX-110 and other anti-GITR antibodies are disclosed, for example, in US 2017/0022284 and WO 2017/015623, which are incorporated by reference in their entirety.
In one embodiment, the GITR agonist (e.g., fusion protein) is MEDI1873 (mediimmune, inc., midi, also known as MEDI 1873). MEDI1873 and other GITR agonists are disclosed in, for example, US 2017/0073386, WO 2017/025610, and Ross et al, Cancer Res [ Cancer research ] 2016; 76(14 suppl) abstract nr 561 (which is incorporated by reference in its entirety). In one embodiment, the GITR agonist comprises one or more of an IgG Fc domain of MEDI1873, a functional multimerization domain, and a receptor binding domain of a glucocorticoid-induced TNF receptor ligand (GITRL).
Additional known GITR agonists (e.g., anti-GITR antibodies) include, for example, those described in WO 2016/054638 (which is incorporated by reference in its entirety).
In one embodiment, the anti-GITR antibody is an antibody that competes with one of the anti-GITR antibodies described herein for binding to and/or binding to the same epitope on GITR.
In one embodiment, the GITR agonist is a peptide that activates the GITR signaling pathway. In one embodiment, the GITR agonist is an immunoadhesin-binding fragment (e.g., an immunoadhesin-binding fragment comprising an extracellular or GITR-binding portion of GITRL) fused to a constant region (e.g., an Fc region of an immunoglobulin sequence).
Table H: amino acid sequences of exemplary anti-GITR antibody molecules
IL15/IL-15Ra complexes
In one aspect of the invention, an inhibitor of IL-1 β or a functional fragment thereof is administered with an IL-15/IL-15Ra complex in some embodiments, the IL-15/IL-15Ra complex is selected from NIZ985 (Nowa), ATL-803 (Altor), or CYP0150 (Cytune).
In one embodiment, the IL-15/IL-15Ra complex comprises human IL-15 complexed to a soluble form of human IL-15 Ra. The complex may comprise a soluble form of IL-15 covalently or non-covalently linked to IL-15 Ra. In specific embodiments, the human IL-15 binds non-covalently to the soluble form of IL-15 Ra. In specific embodiments, the human IL-15 of the composition comprises the amino acid sequence of SEQ ID NO:1001 of Table I and the soluble form of human IL-15Ra comprises the amino acid sequence of SEQ ID NO:1002 of Table I, as described in WO 2014/066527, incorporated by reference in its entirety. These molecules described herein can be made by the vehicles, host cells, and methods described in WO 2007/084342, which is incorporated by reference in its entirety.
TABLE I amino acid and nucleotide sequences of exemplary IL-15/IL-15Ra complexes
In one embodiment, the IL-15/IL-15Ra complex is ALT-803(IL-15/IL-15Ra Fc fusion protein (IL-15N72D: IL-15RaSu/Fc soluble complex)). ALT-803 is disclosed in WO 2008/143794, incorporated by reference in its entirety. In one embodiment, the IL-15/IL-15Ra Fc fusion protein comprises a sequence as disclosed in Table J.
In one embodiment, the IL-15/IL-15Ra complex comprises IL-15 fused to the sushi domain of IL-15Ra (CYP0150, Saiteng pharmaceutical). The sushi domain of IL-15Ra refers to a domain that begins at the first cysteine residue after the signal peptide of IL-15Ra and ends at the fourth cysteine residue after the signal peptide. Complexes of IL-15 fused to the sushi domain of IL-15Ra are disclosed in WO 2007/04606 and WO 2012/175222, which are incorporated by reference in their entirety. In one embodiment, the IL-15/IL-15Ra sushi domain fusion comprises a sequence as disclosed in Table J.
TABLE J amino acid sequences of other exemplary IL-15/IL-15Ra complexes
CTLA-4 inhibitors
In one aspect of the invention, an IL-1 β inhibitor or a functional fragment thereof is administered with a CTLA-4 inhibitor, in some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody or fragment thereof exemplary anti-CTLA-4 antibodies include Tremelimumab (Tremelimumab) (formerly tikitamumab (ticilimumab), CP-675,206), and epilimumab (MDX-010,
In another embodiment, the IL-1 β antibody or functional fragment thereof is gavaglizumab or functional fragment thereof, administered in combination with a PD-1 or PD-L1 inhibitor, said PD-1 or PD-L1 inhibitor preferably being selected from nivolumab, lanolizumab, altrituzumab, avilumab, dovuluzumab and PDR-001/sibatuzumab, in particular with altrituzumab, or in particular with lanolizumab, wherein gavaguzumab is preferably administered in combination with a PD-1 or PD-L1 inhibitor at the same time.
In one embodiment, the patient has a tumor with high PD-L1 expression [ Tumor Proportion Score (TPS) ≧ 50% ], with or without EGFR or ALK genomic tumor abnormalities as determined by FDA-approved testing. In one embodiment, the patient has a tumor with PD-L1 expression (TPS ≧ 1%) as determined by an FDA-approved test.
The term "in combination with … …" is to be understood as the administration of two or more drugs, either subsequently or simultaneously. Alternatively, the term "in combination with … …" should be understood as administering two or more drugs in a manner that contemplates overlapping effective therapeutic concentrations of the drugs over a substantial period of time in a patient. The drug of the invention and one or more combination partners (e.g. another drug, also referred to as "therapeutic agent" or "co-agent") may be administered independently at the same time or separately within time intervals, especially where these time intervals allow the combination partners to show a synergistic (e.g. synergistic) effect. The terms "co-administration" or "combined administration" and the like as used herein are intended to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or simultaneously. The medicaments are administered to the patient simultaneously, concurrently or sequentially, as separate entities, without specific time constraints, wherein such administration provides therapeutically effective levels of both compounds in the patient's body, and the treatment regimen will provide the beneficial effects of the combination of medicaments in treating the conditions or disorders described herein. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.
In one embodiment, the present invention provides an IL-1 β antibody or functional fragment thereof, suitably canargiunumab or functional fragment thereof, for use in treating lung cancer, wherein the lung cancer is advanced, metastatic, recurrent and/or refractory lung cancer.
In one embodiment, the invention provides an IL-1 β antibody or a functional fragment thereof, suitably canargizumab or a functional fragment thereof or gavaglizumab or a functional fragment thereof, for use as a first line treatment of a cancer having at least a partial basis for inflammation, typically a cancer having at least a partial basis for inflammation including, but not limited to, lung cancer (especially NSCLC), colorectal cancer, melanoma, gastric cancer (including esophageal cancer), Renal Cell Carcinoma (RCC), breast cancer, hepatocellular carcinoma (HCC), prostate cancer, bladder cancer, AML, multiple myeloma, head and neck cancer and pancreatic cancer in one embodiment, the invention provides an IL-1 β antibody or a functional fragment thereof, suitably canargizumab or a functional fragment thereof or gavaglizumab or a functional fragment thereof, for use as a first line treatment of a cancer having at least a partial basis for inflammation including lung cancer, especially NSCLC, especially for a patient having IL-1 β or IL-1 receptor expression or overexpression, especially for a patient having IL-1 receptor expression or overexpression of IL-1 receptor before the patient develops resistance to one or more other chemotherapeutic agents, preferably in combination with a chemotherapeutic agent, preferably a single or multiple chemotherapeutic agent, such as a single or targeted combination therapy, preferably a chemotherapeutic inhibitor, e.g. a platinum-1-1 antibody or a chemotherapeutic agent, preferably a chemotherapeutic agent, or a chemotherapeutic agent, such as a chemotherapeutic agent, preferably a single chemotherapeutic agent, or a chemotherapeutic agent, such as a chemotherapeutic agent, preferably a chemotherapeutic agent, for use as a chemotherapeutic agent for treating a chemotherapeutic agent for example, for treating a chemotherapeutic agent for treating a cancer.
In a preferred embodiment, the IL-1 β antibody or a fragment thereof may be used as monotherapy or preferably in combination with standard care (e.g. one or more chemotherapeutic agents, especially with FDA approved therapies for lung cancer, especially NSCLC) as first line therapy as well as in combination with a checkpoint inhibitor, preferably in combination with a checkpoint inhibitor selected from the group consisting of either ranibizumab, lanolizumab and PDR-001/ibratuzumab, preferably avilamumab, doluzumab, and altrituzumab.
In one embodiment, the present invention provides for the use of canargizumab or gavaginzumab (preferably canargizumab) in combination with a PD-1 inhibitor (preferably lanolizumab) for first-line treatment of a patient with NCSLC, more preferably with locally advanced IIIB (not eligible for definitive chemotherapy radiation therapy) or stage IV metastatic non-small cell lung cancer (NSCLC). In one embodiment, the NSCLC is squamous NCSLC. In one embodiment, the NSCLC is non-squamous NCSLC. In one embodiment, the patient does not have any EGFR mutations. In one embodiment, the patient does not carry an ALK translocation. In one embodiment, the patient does not carry any known B-RAF mutations. In one embodiment, the patient does not carry any ROS-1 genetic abnormality. In one embodiment, the canargizumab or gavaginzumab, preferably canargizumab, is administered with one or more chemotherapeutic agents during the maintenance phase, i.e., after the induction phase. In one embodiment, the one or more chemotherapeutic agents in the induction phase is a platinum-based duplex chemotherapy, preferably carboplatin + pemetrexed or preferably cisplatin + pemetrexed. In one embodiment, the one or more chemotherapeutic agents in the induction phase is pemetrexed, wherein preferably the NSCLC is non-squamous. In one embodiment, the one or more chemotherapeutic agents in the induction phase is carboplatin + paclitaxel. In one embodiment, the one or more chemotherapeutic agents in the induction phase is lanolizumab. In one embodiment, only the canargizumab or gavaglizumab (preferably canargizumab) is administered in combination with the PD-1 inhibitor (preferably lanolizumab) during the maintenance phase. In one embodiment, pemetrexed is maintained during maintenance phase, preferably for non-squamous NSCLC. In one embodiment, 200mg of canargizumab is administered every three weeks. If there is a safety hazard, it can be titrated down to 200mg every 6 weeks. In one embodiment, the Progression Free Survival (PFS) of the group of patients receiving canargizumab or gavagizumab is at least 2 months, at least 3 months, or at least 4 months longer than the placebo group receiving standard of care without canargizumab or gavagizumab, wherein the patient does not receive canargizumab. In one embodiment, the group of patients receiving treatment with geckiizumab has a relative risk reduction of 80% or less, preferably 70% or less, preferably 60% or less, compared to the placebo group receiving standard of care without nagogic nonamab or geckiizumab.
Progression-free survival (PFS) according to RECIST 1.1 was compared to Overall Survival (OS) for both treatment groups (canajirimumab versus placebo).
In a preferred embodiment, gavoglizumab or a fragment thereof in combination with a checkpoint inhibitor, preferably with a PD-1/PD-L1 inhibitor (selected from nivolumab, lanolizumab and PDR-001/sibatuzumab, avilumab, dovuzumab and alemtuzumab, preferably alemtuzumab) is used as first line therapy for lung cancer, in particular NSCLC. In a preferred embodiment, the checkpoint inhibitor is lanolizumab. In a preferred embodiment, the checkpoint inhibitor is sibutrumab. In another preferred embodiment, at least one further chemotherapeutic agent, preferably a platinum agent, e.g. cisplatin or a mitotic inhibitor, e.g. docetaxel, is additionally added to the above combination. In one embodiment, gavaglizumab is administered sequentially or preferably simultaneously with checkpoint inhibitor at a dose of 60mg to 90mg every 3 or 4 weeks, or a dose of 120mg every 3 or 4 weeks, or a dose of 90mg every 3 or 4 weeks, preferably intravenously.
In one embodiment, the present invention provides an IL-1 β antibody or a functional fragment thereof, suitably canargizumab or a functional fragment thereof, for use as a second or third line therapy for cancers with at least a partial basis for inflammation, including lung cancer, especially NSCLC.
For use as a second-or third-line therapy, the IL-1 β antibody or a functional fragment thereof (such as canargizumab or gavaglizumab) can be administered to a patient as monotherapy or preferably in combination with a checkpoint inhibitor (particularly a PD-1 or PD-L1 inhibitor, particularly altritizumab), with or without one or more small molecule chemotherapeutic agents.
In a preferred embodiment the canargizumab or fragment thereof is used in a second or third line therapy for lung cancer, especially NSCLC, in combination with a checkpoint inhibitor, preferably a checkpoint inhibitor selected from nivolumab, lanreozumab and PDR-001/sibatuzumab (Novartis), epirubizumab and alemtuzumab, preferably alemtuzumab, in a preferred embodiment the checkpoint inhibitor is lanreolizumab in a preferred embodiment the checkpoint inhibitor is sibatuzumab in a further preferred embodiment in the above combination additionally at least one further chemotherapeutic agent, preferably a platinum agent, such as cisplatin or a mitotic inhibitor, such as docetaxel in an embodiment the canargizumab is administered at a dose of 200mg every 3 weeks, preferably subcutaneously, sequentially or preferably simultaneously with the checkpoint inhibitor.
In a preferred embodiment, canargiunumab or gembizumab is used in combination with one or more chemotherapeutic agents, preferably the mitotic inhibitor docetaxel, as a second or third line treatment of lung cancer, in particular NSCLC. In one embodiment, the NSCLC is squamous NCSLC. In one embodiment, the NSCLC is non-squamous NCSLC. In one embodiment, the patient has locally advanced (stage IIIB) or metastatic (stage IV) NSCLC. In one embodiment, the patient does not have any EGFR mutations. In one embodiment, the patient does not carry an ALK translocation. In one embodiment, the patient does not carry any known B-RAF mutations. In one embodiment, the patient does not carry any ROS-1 genetic abnormality. In one embodiment, the patient is resistant to treatment with a checkpoint inhibitor, preferably a PD-1 or PD-L1 inhibitor. In one embodiment, the patient is resistant to treatment with platinum-based chemotherapy. In one embodiment, the patient is resistant to treatment with platinum-based chemotherapy in conjunction with a checkpoint inhibitor, preferably a PD-1 or PD-L1 inhibitor. In one embodiment, 200mg of canargizumab is administered every 3 weeks. If there is a safety hazard, it can be titrated down to 200mg every 6 weeks. In one embodiment, the patient receives s.c every 3 weeks or every 6 weeks for 200mg of canargiunumab plus 75mg/m2 i.v. docetaxel every 1 day of a 21 day cycle (Q3W). In one embodiment, the OS risk rate in the patient group treated with docetaxel plus canaryitumumab is reduced by at least 25%, preferably at least 35%, or at least 43%, i.e. the expected risk ratio is 0.57 (under the index model assumption, this corresponds to an increase in median OS to 14 months compared to 8 months survival in the docetaxel group alone.
In a preferred embodiment, gavagizumab, or a functional fragment thereof, is used in combination with a checkpoint inhibitor, preferably with a PD-1/PD-L1 inhibitor selected from nivolumab, lanolizumab and PDR-001/sibatuzumab (nova corporation) and altrituzumab, preferably altrituzumab, more preferably lanolizumab, as a second or third line treatment of lung cancer, in particular NSCLC or colorectal cancer. In another preferred embodiment, at least one further chemotherapeutic agent, preferably a platinum agent, e.g. cisplatin or a mitotic inhibitor, e.g. docetaxel, is additionally added to the above combination. In one embodiment, gavoglizumab is administered at a dose of 60mg to 90mg every 3 or 4 weeks, or a dose of 120mg every 3 or 4 weeks, preferably intravenously, sequentially or simultaneously with the checkpoint inhibitor.
In one embodiment, the present invention provides an IL-1 β antibody or a functional fragment thereof for use as an adjunct therapy in treating lung cancer in a subject after standard care at each stage, wherein the patient has high risk NSCLC (IB, 2 or 3A stage), wherein the lung cancer has been surgically resected (surgically resected). in one embodiment, the adjunct therapy will last for at least 6 months, preferably at least one year, preferably one year.
In one embodiment, the present invention provides that canaryitumumab or a functional fragment thereof is used as an adjunct therapy to treat lung cancer in a subject after surgical removal of lung cancer, preferably the patient has completed a standard chemotherapeutic treatment, e.g., 4 cycles of cisplatin-based chemotherapy in one embodiment, canaryitumumab is administered at a dose of 200mg, preferably at least one year in one embodiment, canaryitumumab is administered at a dose of 200mg every 3 weeks or month, preferably subcutaneously, preferably for at least one year in another embodiment, the present invention provides an IL-1 β antibody or a functional fragment, used as a first line therapy for NSCLC in a patient alone or preferably in combination with standard care, wherein the patient has a stage 3B (not suitable for chemotherapy/chemotherapy) or a stage 4 disease, in one embodiment, the IL-1 β antibody or a functional fragment thereof is a geckunjikutkatuzumab in one embodiment, the IL-1 β antibody or a functional fragment thereof is a canaryitumumab or a functional fragment thereof is a single dose of a chemotherapeutic agent, preferably a chemotherapeutic agent, or a monthly dose of one or more than one or a monthly dose of a chemotherapeutic agent, preferably a chemotherapeutic agent, a single dose of 200mg or a monthly, preferably a monthly, a monthly dose of a chemotherapeutic agent, or a monthly, wherein the patient is administered at least one dose of a monthly dose of a chemotherapeutic agent selected from about 200mg of a chemotherapeutic agent, preferably a chemotherapeutic agent, preferably a chemotherapeutic agent, in another embodiment, a chemotherapeutic agent, preferably a chemotherapeutic agent, preferably a chemotherapeutic agent, in one embodiment, a chemotherapeutic agent, in another embodiment, a weekly chemotherapeutic agent, a monthly embodiment, a non-1-300, a non-1, a non-300, a non-1, a non-300, a non-1, a non-treating a non-300, a non-1, a non-treating a non-.
In one embodiment, the present invention provides an IL-1 β antibody or a functional fragment thereof for use as a monotherapy or preferably in combination with standard care in treating colorectal (CRC) or gastro-intestinal cancer in a patient, in one embodiment, the IL-1 β antibody or a functional fragment thereof is gavagizumab, in one embodiment, gavagizumab is administered at a dose of 60mg to 90mg per treatment, wherein gavagizumab is preferably administered every 3 weeks or preferably monthly, in one embodiment, gavagizumab is administered at a dose of 120mg per treatment, wherein gavagizumab is preferably administered every 3 weeks or preferably monthly.
In a preferred embodiment, the anti-PD-1 antibody molecule is PDR 001/steviolzumab.
In a preferred embodiment, the anti-PD-1 antibody molecule is lanolizumab.
In a preferred embodiment, the anti-PD-1 antibody molecule is altritlizumab.
In a preferred embodiment, the anti-PD-1 antibody molecule is nivolumab.
In certain embodiments, the present invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably gavoglizumab or a functional fragment thereof, suitably canargizumab or a functional fragment thereof, for use in the treatment of Renal Cell Carcinoma (RCC) — the term "Renal Cell Carcinoma (RCC)" as used herein refers to a renal cancer derived from the intrarenal tubular epithelium in the renal cortex and includes primary renal cell carcinoma, locally advanced renal cell carcinoma, unresectable renal cell carcinoma, metastatic renal cell carcinoma, refractory renal cell carcinoma, and/or drug-resistant renal cell carcinoma.
Preferred for first line systemic clear cell RCC are sunitinib, pazopanib, bevacizumab in combination with interferon, and sirolimus in low risk population patients (NCCN guideline 2018). Results from the CheckMate214 study showed that nivolumab in combination with ipilimumab improved ORR and OS compared to sunitinib, resulting in FDA recent approval of this combination for first line treatment of middle and low risk advanced untreated RCC (Motzer et al 2018). Therefore, it is expected that nivolumab in combination with ipilimumab will be the preferred first line treatment regimen for moderate and low risk metastatic RCC patients. For subsequent treatment of patients with predominantly clear cell RCC, clinical guidelines recommend cabozantinib, nivolumab, electroluminixin in combination with everolimus and axitinib treatment as a preferred option (Bamias et al 2017, NCCN guideline 2018).
Cabozantinib, a small molecule inhibitor of tyrosine kinases such as VEGF, MET and AXL, was studied as a second line therapy in a stage III methor trial, where 658 patients receiving prior tyrosine kinase inhibitor pretreatment were randomly assigned (1:1) to 60mg/d oral cabozantinib or 10mg/d oral everolimus, according to the study conducted, for patients with clear cell metastatic RCC after failure of prior anti-angiogenic therapy, cabozantinib or the immune checkpoint inhibitor nivolumab was generally suggested as a preferred follow-up treatment option (Jain et al 2017) as well as rational use of cabozantinib (a tyrosine kinase inhibitor involved in angiogenesis) as a backbone for treatment of patients with metastatic RCC in combination with gevzozumab in this study due to the potential for synergistic anti-tumor effects by reducing angiogenesis and modulating immune responses by double blocking VEGF and IL-1 β signaling in the tumor microenvironment.
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat renal cell carcinoma. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month. In one embodiment, the canarginoumab is administered at a dose of 200mg every 3 weeks or month, preferably subcutaneously. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly. In one embodiment, the gavojizumab is administered at a dose of 120mg every 3 weeks or month, preferably intravenously.
In one embodiment, the present invention provides gavagizumab, or a functional fragment thereof, for use in the treatment of Renal Cell Carcinoma (RCC), wherein gavagizumab, or a functional fragment thereof, is administered in combination with one or more therapeutic agents, e.g., a chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is a standard of care agent for Renal Cell Carcinoma (RCC). In one embodiment, the one or more chemotherapeutic agents are selected from everolimus
In one embodiment, the one or more therapeutic agents is a CTLA-4 checkpoint inhibitor, wherein preferably, the CTLA-4 checkpoint inhibitor is epilimumab. In one embodiment, the one or more chemotherapeutic agents is everolimus.
In one embodiment, the one or more therapeutic agents are checkpoint inhibitors, wherein PD-1 or PD-L1 inhibitors are preferred, wherein preferably selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
In one embodiment, the one or more therapeutic agents is nivolumab. In one embodiment, the one or more chemotherapeutic agents is nivolumab plus epilinumab.
In one embodiment, the one or more chemotherapeutic agents is cabozantinib.
In one embodiment, the one or more therapeutic agents, e.g., a chemotherapeutic agent, is altritlizumab plus bevacizumab.
In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to prevent the recurrence or recurrence of Renal Cell Carcinoma (RCC) in a patient after the cancer has been surgically resected. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination in the first line treatment of Renal Cell Carcinoma (RCC). In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination in the second or third line treatment of Renal Cell Carcinoma (RCC). In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination to treat metastatic RCC.
In one embodiment, gavojizumab or a functional fragment thereof is used in combination with cabozantinib for the treatment of advanced renal cell carcinoma.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
In certain embodiments, the present invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably gavaglizumab or a functional fragment thereof, suitably canargizumab or a functional fragment thereof, for use in the treatment of colorectal cancer (CRC) — the term "colorectal cancer (CRC)", also known as intestinal cancer and colon cancer, as used herein, refers to tumors derived from the colon and/or rectum, particularly from the colon and/or rectal epithelium, and includes colorectal adenocarcinoma, rectal adenocarcinoma, metastatic colorectal cancer (mCRC), advanced colorectal cancer, refractory metastatic microsatellite stabilization (MSS) colorectal cancer, non-resectable colorectal cancer and/or cancer drug resistant colorectal cancer.
Typically, the initial treatment of the disease involves a cytotoxic backbone of a dual chemotherapy regimen using fluoropyrimidine (5-fluorouracil or capecitabine) in combination with oxaliplatin (FOLFOX or xeloxx) or irinotecan (FOLFIRI).
Bevacizumab (anti-Vascular Endothelial Growth Factor (VEGF) monoclonal antibody (mAb)), cetuximab (anti-Epidermal Growth Factor Receptor (EGFR) mAb) and panitumumab (anti-EGFR mAb) are the only targeted therapies for mCRC pancreatic therapy currently combined with backbone chemotherapy. anti-EGFR therapies cetuximab and panitumumab are limited to Ras wild-type tumor patients, while bevacizumab can be used regardless of Ras mutation status. NO16966 phase III randomized trial, initially designed to compare the standard FOLFOX-4 (oxaliplatin, fluorouracil and tetrahydrofolic acid) regimen with XELOX (oxaliplatin and capecitabine), and later modified to a 2 x 2 factorial design to incorporate bevacizumab, demonstrated the benefit of adding bevacizumab to the oxaliplatin-containing regimen.
The current standard of care for first-line mCRC patients with Ras wild-type tumors is cetuximab or bevacizumab in combination with FOLFOX or FOLFIRI.
For the treatment of second-line mCRC, it is suggested to switch the chemotherapy backbone so that if patients are treated in the first line using FOLFOX or XELOX based regimens, FOLFIRI should be used in the second line. Alternatively, if FOLFIRI is used in the first line case, FOLFOX or XELOX will be the preferred partner in the first line. Multiple second-line studies have shown that the addition of anti-angiogenic agents (e.g., bevacizumab) is beneficial in chemotherapy. These data further expand the indications for bevacizumab and can be used to treat second-line patients who have progressed on the first-line bevacizumab-containing regimen.
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat CRC. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month. In one embodiment, the canarginoumab is administered at a dose of 200mg every 3 weeks or month, preferably subcutaneously. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly. In one embodiment, the gavojizumab is administered at a dose of 120mg every 3 weeks or month, preferably intravenously.
In one embodiment, the present invention provides gavaglus mab or functional fragment thereof for use in treating colorectal cancer (CRC), wherein gavaglus mab or functional fragment thereof is administered in combination with one or more therapeutic agents, such as a chemotherapeutic agent. In one embodiment, the therapeutic agent, e.g., chemotherapeutic agent, is a standard of care agent for CRC. In one embodiment, the one or more chemotherapeutic agents are selected from irinotecan hydrochloride
In one embodiment, the one or more chemotherapeutic agents are general cytotoxic agents, wherein preferably the general cytotoxic agents are selected from the list consisting of: FOLFOX, FOLFIRI, capecitabine, 5-fluorouracil, irinotecan and oxaliplatin.
Typically, the initial treatment for CRC involves the cytotoxic scaffold of a dual chemotherapy regimen using fluorouracil and oxaliplatin (FOLFOX), fluorouracil and irinotecan (FOLFIRI) or capecitabine and oxaliplatin (XELOX) in combination. It is generally recommended to first combine bevacizumab with chemotherapy. For patients with wild-type RAS tumors, anti-EGFR agents (cetuximab and/or panitumumab) are an alternative to the combination of primary biologic therapy with diaphyseal chemotherapy.
As used herein, the term "FOLFOX" refers to a combination therapy (e.g., chemotherapy) comprising at least one oxaliplatin compound (selected from the group consisting of oxaliplatin, pharmaceutically acceptable salts thereof and solvates of any of the foregoing); at least one 5-fluorouracil (also known as 5-FU) compound (selected from 5-fluorouracil, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing); at least one folinic acid compound selected from folinic acid (also known as tetrahydrofolic acid), levofolic acid (the levorotatory isoform of folinic acid), pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. The term "FOLFOX" as used herein is not intended to be limited to any specific amount or dosing regimen of those components.
As used herein, the term "FOLFIRI" refers to a combination therapy (e.g., chemotherapy) comprising at least one irinotecan compound (selected from irinotecan, its pharmaceutically acceptable salts, and solvates of any of the foregoing); at least one 5-fluorouracil (also known as 5-FU) compound (selected from 5-fluorouracil, pharmaceutically acceptable salts thereof, and solvates of any of the foregoing); at least one compound selected from the group consisting of folinic acid (also known as tetrahydrofolic acid), levofolic acid (the levorotatory isoform of folinic acid), pharmaceutically acceptable salts of any of the foregoing, and solvates of any of the foregoing. The term "FOLFIRI" as used herein is not intended to be limited to any particular amount or dosing regimen of these components. Rather, as used herein, "FOLFIRI" includes all combinations of these components in any number and dosing regimen.
In one embodiment, the one or more chemotherapeutic agents are VEGF inhibitors (e.g., inhibitors of one or more of VEGFR (e.g., VEGFR-1, VEGFR-2, or VEGFR-3) or VEGF).
Exemplary VEGFR pathway inhibitors that may be used in combination with IL-1 β binding antibodies or functional fragments thereof (suitably gavoglizumab) for the treatment of cancer, particularly cancers with a partial basis of inflammation include, for example, bevacizumab (also known as rhuMAb VEGF or rhuMAb)
In one embodiment, the one or more chemotherapeutic agents is an anti-VEGF antibody. In one embodiment, the one or more chemotherapeutic agents are small molecular weight anti-VEGF inhibitors.
In one embodiment, the one or more chemotherapeutic agents is a VEGF inhibitor selected from the list consisting of: bevacizumab, ramucirumab and aflibercept. In a preferred embodiment, the VEGF inhibitor is bevacizumab.
In one embodiment, the one or more chemotherapeutic agents is FOLFIRI plus bevacizumab or FOLFOX plus bevacizumab or xeloxx plus bevacizumab.
In one embodiment, the one or more therapeutic agents are for example checkpoint inhibitors, preferably PD-1 or PD-L1 inhibitors, preferably selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001). In a preferred embodiment, the one or more therapeutic agents is lanolizumab. In a preferred embodiment, the one or more chemotherapeutic agents is nivolumab.
In a preferred embodiment, the one or more therapeutic agents is altrituximab. In another preferred embodiment, the one or more therapeutic agents, e.g., chemotherapeutic agents, are altlizumab and cabitinib.
In a preferred embodiment, the one or more chemotherapeutic agents is ramucirumab. In a preferred embodiment, the patient has metastatic CRC.
In a preferred embodiment, the one or more chemotherapeutic agents is aflibercept. In a preferred embodiment, the patient has metastatic CRC.
In a preferred embodiment, the one or more chemotherapeutic agents are tyrosine kinase inhibitors. In one embodiment, the tyrosine kinase inhibitor is an EGF pathway inhibitor, preferably an epidermal growth factor receptor inhibitor (EGFR) inhibitor. Preferably the EGFR inhibitor is selected from one or more of: erlotinib
In one embodiment, the EGFR inhibitor is (R, E) -N- (7-chloro-1- (1- (4- (dimethylamino) but-2-enoyl) azepan-3-yl) -1H-benzo [ d ] imidazol-2-yl) -2-methylisonicotinamide (compound a40) or a compound disclosed in PCT publication No. WO 2013/184757.
In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to prevent the recurrence or recurrence of CRC in a patient after the cancer has been surgically resected. In one embodiment, the gemfibrozumab or functional fragment thereof is used alone or preferably in combination in the first line treatment of CRC. In one embodiment, the gemfibrozumab or functional fragment thereof is used alone or preferably in combination in the second or third line treatment of CRC. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to treat metastatic CRC.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in combination with FOLFOX and bevacizumab for use in first line metastatic CRC treatment, wherein 30mg to 120mg of gavoglizumab or a functional fragment thereof is administered every 4 weeks.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in combination with FOLFIRI and bevacizumab for second line metastatic CRC treatment, wherein gavoglizumab or a functional fragment thereof is administered every 4 weeks.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
In certain embodiments, the invention provides an IL-1 β antibody or functional fragment thereof, suitably gavojizumab or a functional fragment thereof, suitably canajirimumab or a functional fragment thereof, for use in the treatment of gastric cancer.
As used herein, the term "gastric cancer" includes gastric and intestinal cancers as well as esophageal cancer (gastroesophageal cancer), particularly the lower portion of the esophagus, and refers to primary gastric cancer, metastatic gastric cancer, refractory gastric cancer, unresectable gastric cancer, and/or cancer drug resistant gastric cancer. The term "gastric cancer" includes adenocarcinoma of the distal esophagus, gastroesophageal junction and/or stomach, gastrointestinal carcinoids and gastrointestinal stromal tumors. In a preferred embodiment, the gastric cancer is gastroesophageal cancer.
Patients with unresectable or metastatic gastric and/or gastroesophageal junction adenocarcinoma are candidates for only palliative chemotherapy treatment. First line therapy includes platinum agents and fluoropyrimidines, sometimes with the addition of a third drug, such as anthracyclines or taxanes (Pericay 2016).
The incidence of febrile neutropenia of
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat gastric cancer. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month. In one embodiment, the canargiunumab is administered at a dose of 200mg every 3 or 4 weeks, preferably subcutaneously. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly. In one embodiment, the gavojizumab is administered at a dose of 120mg every 3 weeks or month, preferably intravenously.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in the treatment of gastric cancer, wherein gavoglizumab or a functional fragment thereof is administered in combination with one or more therapeutic agents, e.g., a chemotherapeutic agent. In one embodiment, the therapeutic agent, e.g., chemotherapeutic agent, is a standard of care agent for gastric cancer. In one embodiment, the one or more chemotherapeutic agents are selected from carboplatin plus paclitaxel
In one embodiment, the one or more chemotherapeutic agents are paclitaxel and ramucirumab. In another embodiment, the combination is used for second line treatment of metastatic gastroesophageal cancer.
In one embodiment, the one or more therapeutic agents are checkpoint inhibitors, wherein PD-1 or PD-L1 inhibitors are preferred, wherein preferably selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
In one embodiment, the one or more therapeutic agents is nivolumab. In one embodiment, the one or more chemotherapeutic agents is nivolumab plus epilinumab. In another embodiment, the combination is used for first or second line treatment of metastatic gastroesophageal cancer.
In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to prevent the recurrence or relapse of gastric cancer in a patient after the cancer has been surgically resected. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination in the first line treatment of gastric cancer. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination in the second or third line treatment of gastric cancer. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to treat metastatic gastric cancer. In one embodiment, gavaglizumab, or a functional fragment thereof, alone or preferably in combination, is used to treat second-line metastatic gastroesophageal cancer, wherein the patient typically has locally advanced, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, typically not squamous cell gastric cancer or undifferentiated gastric cancer.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
In certain embodiments, the present invention provides an IL-1 β antibody or functional fragment thereof, suitably gavogeuzumab or a functional fragment thereof, suitably canagenumumab or a functional fragment thereof, for use in treating melanoma the term "melanoma" includes "malignant melanoma" and "cutaneous melanoma" and, as used herein, refers to malignant tumors caused by melanocytes derived from the neural crest although most melanomas occur in the skin, they may also originate at the mucosal surface or other sites to which neural crest cells migrate.
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat melanoma. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month, preferably subcutaneously. In one embodiment, the canargizumab is administered at a dose of 200mg every 3 or 4 weeks. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly, preferably intravenously. In one embodiment, gemfibrozumab is administered at a dose of 90mg every 3 weeks or monthly. In one embodiment, gavoglizumab is administered at a dose of 120mg every 3 weeks or monthly.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in the treatment of melanoma, wherein gavoglizumab or a functional fragment thereof is administered in combination with one or more chemotherapeutic agents. In one embodiment, the chemotherapeutic agent is a standard of care agent for melanoma. In one embodiment, the one or more chemotherapeutic agents are selected from temozolomide, albumin-bound paclitaxel, cisplatin, carboplatin, vinblastine, aldesleukin
Immunotherapy currently under development has begun to provide significant benefits to melanoma cancer patients, including patients for whom conventional therapy is not effective. More recently, lanolizumab
In one embodiment, the one or more therapeutic agents is epilimumab.
In one embodiment, the one or more therapeutic agents (e.g., chemotherapeutic agents) are nivolumab and epirubizumab.
In one embodiment, the one or more chemotherapeutic agents is trametinib.
In one embodiment, the one or more chemotherapeutic agents is dabrafenib.
In one embodiment, the one or more chemotherapeutic agents are trametinib and dabrafenib.
In one embodiment, the one or more chemotherapeutic agents is lanolizumab.
In one embodiment, the one or more chemotherapeutic agents is atelizumab.
In one embodiment, the one or more chemotherapeutic agents is atelizumabBevacizumab is added.
In one embodiment, the gavojizumab or functional fragment thereof is used alone or preferably in combination to prevent the recurrence or recurrence of melanoma in a patient after the cancer has been surgically resected. In one embodiment, the gemfibrozumab or functional fragment thereof is used alone or preferably in combination in the first line treatment of melanoma. In one embodiment, the gavoglizumab or functional fragment thereof is used alone or preferably in combination in the second or third line treatment of melanoma. In one embodiment, gavojizumab or a functional fragment thereof is used alone or preferably in combination to treat metastatic melanoma.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
As already observed with regard to the role of IL-1 β in the development of lung cancer, it is also reasonable that IL-1 β plays a similar role in the development of melanoma.
The activation of caspase-1 by tumor cells expressing The precursor of IL-1 β must first activate caspase-1 to process inactive precursors into active cytokines The activation of caspase-1 requires autocatalysis of caspase-1 by The nucleotide binding domain and The protein 3(NLRP3) inflammasome containing The leucine rich repeat sequence (Dinarello, C.A. (2009) AnnRev Immunol [ Ann. Rev. Immunol ],27, 519-550.) in late stage human melanoma cells, spontaneous secretion of active IL-1 β was observed by constitutive activation of NLRP3 inflammasome (Okamoto, M. et al, The Journal of Biological Chemistry, 285, 6477-6488. unlike human liquid mononuclear cells, which do not require exogenous stimulation, in contrast, The function of NLRP3 in intermediate stage melanoma cells requires activation of IL-1 α to promote The production of IL-1 by The spontaneous secretion of IL-1 receptor kinase in vitro Biochemcial Biochequer [ IL-1. J.,. Biochemcial Chemistry ],285, 6488 ] in contrast to The development of melanoma cells which was observed by The spontaneous secretion of IL-1-macrophage cell biopsy and which was not able by The intracellular leukocyte cell line expressed by IL-2, mRNA-mediated by The intracellular leukocyte cell line (IL-mediated by The biochemical pathway of IL-mediated tumor cells).
Thus, in one aspect, the invention provides an IL-1 β binding antibody or a functional fragment thereof (e.g., canargizumab or gavaglizumab) for use in the treatment and/or prevention of melanoma in a patient in one embodiment, the patient has equal to or greater than 2mg/L or equal to or greater than 4mg/L of high sensitivity C-reactive protein (hsCRP).
In one embodiment, about 90mg to about 450mg of IL-1 β binding antibody or functional fragment thereof is administered to a melanoma patient per treatment, preferably every two, three or four weeks (monthly).
In one embodiment, the IL-1 β binding antibody is canargiunumab, preferably 300mg of canargiunumab per month, furthermore, the second administration of canargiunumab is up to two weeks, preferably two weeks, from the first administration.
In one embodiment, the IL-1 β binding antibody is gavoglizumab (XOMA-052).
In addition, lung cancer has concomitant inflammation activated or is mediated in part by activation of the Nod-like receptor protein 3(NLRP3) inflammasome and thereby causes local interleukin-1 β production it is reasonable from the standpoint of IL-1 β involvement in cancer development that melanoma has a similar mechanism.
All the teachings disclosed in the present application regarding the use of IL-1 β binding antibodies or functional fragments thereof, in particular cana-or gavageven-mab, in the treatment and/or prevention of melanoma, in particular regarding the dosing regimen of cana-or gavageven-mab, in particular regarding the level of hsCRP in the patient and its reduction by treatment, in particular regarding the use of hsCRP as biomarker, are equally applicable or can be easily modified by the skilled person.
In certain embodiments, the present invention provides an IL-1 β binding antibody or functional fragment thereof, suitably Gevogeuzumab, or functional fragment thereof, suitably Canagagumab, or functional fragment thereof, for use in the treatment of bladder cancer As used herein, the term "bladder cancer" refers to squamous cell bladder cancer, adenocarcinoma of the bladder, small cell carcinoma of the bladder, and urothelial (cellular) cancer, i.e., bladder cancer, ureteral cancer, renal pelvis cancer, and cancer of the urethra.
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat bladder cancer. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month. In one embodiment, the canargiunumab is administered at a dose of 200mg every 3 weeks or every 4 weeks, preferably subcutaneously. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly. In one embodiment, the gavojizumab is administered at a dose of 120mg every 3 weeks or month, preferably intravenously.
Treatment regimens for bladder cancer include intravesical treatment of early stage bladder cancer and chemotherapy with or without radiotherapy.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in the treatment of bladder cancer, wherein gavoglizumab or a functional fragment thereof is administered in combination with one or more chemotherapeutic agents. In one embodiment, the chemotherapeutic agent is a standard of care agent for bladder cancer. In one embodiment, the one or more chemotherapeutic agents are selected from cisplatin, cisplatin + fluorouracil (5-FU), mitomycin plus 5-FU, gemcitabine plus cisplatin, MVAC (methotrexate, vinblastine, adriamycin)Plain (doxorubicin), cisplatin), CMV (cisplatin, methotrexate and vinblastine), carboplatin plus paclitaxel or docetaxel, gemcitabine, cisplatin, carboplatin, docetaxel, paclitaxel, doxorubicin, 5-FU, methotrexate, vinblastine, ifosfamide, pemetrexed, thiotepa, valrubicin, alemtuzumab
Depending on the condition of the patient, at least one, at least two or at least three chemotherapeutic agents may be selected from the above list, in combination with the gemfibrozumab.
In one embodiment, the one or more therapeutic agents are checkpoint inhibitors, wherein PD-1 or PD-L1 inhibitors are preferred, wherein preferably selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
In one embodiment, the gavojizumab or functional fragment thereof is to prevent recurrence or recurrence of bladder cancer in the patient after the cancer has been surgically resected. In one embodiment, the gemfibrozumab or functional fragment thereof is used alone or preferably in combination in the first line treatment of bladder cancer. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination in the second or third line treatment of bladder cancer. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination to treat metastatic bladder cancer.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
The term "prostate cancer" as used herein refers to acinar adenocarcinoma, ductal adenocarcinoma, squamous cell prostate carcinoma, small cell prostate carcinoma and includes prostate cancer sensitive to androgen deficiency/castration, prostate cancer resistant to androgen deficiency/castration, primary prostate cancer, locally advanced prostate cancer, unresectable prostate cancer, metastatic prostate cancer, refractory prostate cancer, recurrent prostate cancer and/or cancer drug resistant prostate cancer.
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat prostate cancer. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month. In one embodiment, the canargiunumab is administered at a dose of 200mg every 3 weeks or every 4 weeks, preferably subcutaneously. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly. In one embodiment, the gavojizumab is administered at a dose of 120mg every 3 weeks or month, preferably intravenously.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in the treatment of prostate cancer, wherein gavoglizumab or a functional fragment thereof is administered in combination with one or more therapeutic agents, e.g., a chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is a standard of care agent for prostate cancer. In one embodiment, the one or more chemotherapeutic agents are selected from abiraterone, apalutamide (apalcuamide), bicalutamide, cabazitaxel, degarelix, docetaxel, c,Docetaxel plus prednisone, enzalutamide
Depending on the condition of the patient, at least one, at least two or at least three chemotherapeutic agents may be selected from the above list, in combination with the gemfibrozumab.
In one embodiment, the one or more therapeutic agents are checkpoint inhibitors, wherein PD-1 or PD-L1 inhibitors are preferred, wherein preferably selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
In one embodiment, the gavojizumab or functional fragment thereof is for preventing recurrence or recurrence of prostate cancer in a patient after the cancer has been surgically resected. In one embodiment, the gemfibrozumab or functional fragment thereof is used alone or preferably in combination in the first line treatment of prostate cancer. In one embodiment, gavaglizumab, or a functional fragment thereof, is used alone or, preferably, in combination in the second or third line treatment of prostate cancer. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination to treat metastatic prostate cancer.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
In certain embodiments, the present invention provides an IL-1 β binding antibody or functional fragment thereof, suitably gavoglizumab or a functional fragment thereof, suitably canargizumab or a functional fragment thereof, for the treatment of breast cancer the term "breast cancer" as used herein includes breast cancer arising from ductal (ductal, including invasive ductal and ductal in situ cancer (DCIS)), glandular (lobular, including invasive lobular and lobular in situ cancer (LCIS)), inflammatory breast cancer, angiosarcoma, and includes, but is not limited to, estrogen receptor positive (ER +) breast cancer, progesterone receptor positive (PR +) breast cancer, herceptin receptor positive (HER2+) breast cancer, herceptin receptor negative (HER2-) breast cancer, ER positive/HER 2 negative breast cancer and triple negative breast cancer (TNBC; HER2-, ER-and PR-breast cancer).
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat breast cancer. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month. In one embodiment, the canargiunumab is administered at a dose of 200mg every 3 weeks or every 4 weeks, preferably subcutaneously. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly. In one embodiment, the gavojizumab is administered at a dose of 120mg every 3 weeks or month, preferably intravenously.
Treatment regimens for breast cancer include intravesical treatment of early stage breast cancer and chemotherapy with or without radiotherapy.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in the treatment of breast cancer, wherein gavoglizumab or a functional fragment thereof is administered in combination with one or more therapeutic agents, e.g., a chemotherapeutic agent. In one embodiment, the therapeutic agent, e.g., chemotherapeutic agent, is a standard of care agent for breast cancer. In one embodiment, the one or more therapeutic agents, e.g., chemotherapeutic agents, are selected from the group consisting of abeticide, methotrexate, abbrevitalin (paclitaxel albumin stabilized nanoparticle formulation), ado-trastuzumab, anastrozole, pamidronate disodium oxazole, capecitabineBib, cyclophosphamide, docetaxel, epirubicin hydrochloride, eribulin mesylate, exemestane, fluorouracil injection, fulvestrant, gemcitabine hydrochloride, goserelin acetate, ixabepilone, lapatinib ditosylate, letrozole, megestrol acetate, methotrexate, lenatinib maleate, olaparib, paclitaxel, disodium pamidronate, tamoxifen, thiotepa, toremifene, vinblastine sulfate, AC (epirubicin hydrochloride (doxorubicin ylidene) and cyclophosphamide), AC-T (epirubicin hydrochloride (doxorubicin), cyclophosphamide and paclitaxel), CAF (cyclophosphamide, epirubicin hydrochloride (doxorubicin), and fluorouracil), CMF (cyclophosphamide, methotrexate, and fluorouracil), FEC (fluorouracil, epirubicin hydrochloride, doxorubicin hydrochloride, and fluxol), and their salts, Cyclophosphamide), TAC (docetaxel (taxotere), epirubicin hydrochloride (doxorubicin), cyclophosphamide), palbociclib, Abesib, Ribociclib, Everolimus, trastuzumab
Depending on the condition of the patient, at least one, at least two or at least three chemotherapeutic agents may be selected from the above list, in combination with the gemfibrozumab.
In one embodiment, the one or more therapeutic agents are checkpoint inhibitors, wherein PD-1 or PD-L1 inhibitors are preferred, wherein preferably selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
In a preferred embodiment, the IL-1 β antibody or functional fragment thereof, preferably canargizumab or gavagezumab, is used in combination with one or more chemotherapeutic agents, wherein the chemotherapeutic agent is an anti-Wnt inhibitor, preferably myristyl mab this embodiment is particularly useful in inhibiting breast tumor metastasis.
In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to prevent the recurrence or recurrence of breast cancer in a patient after the cancer has been surgically resected. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination in the first line treatment of breast cancer. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or preferably in combination in the second or third line treatment of breast cancer. In one embodiment, gemfibrozumab or a functional fragment thereof is used alone or preferably in combination in the treatment of TNBC. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to treat metastatic breast cancer.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
In certain embodiments, the invention provides an IL-1 β binding antibody or a functional fragment thereof, suitably gavojizumab or a functional fragment thereof, suitably canajirimumab or a functional fragment thereof, for use in the treatment of pancreatic cancer.
As used herein, the term "pancreatic cancer" refers to pancreatic endocrine and pancreatic exocrine tumors and includes adenocarcinomas derived from the pancreatic ductal epithelium, suitably Pancreatic Ductal Adenocarcinoma (PDAC) or tumors derived from pancreatic islet cells, and includes pancreatic neuroendocrine tumors (pNET), such as, for example, gastrinomas, insulinomas, glucagomas, ghrelinas, and somatostatinomas. The pancreatic cancer can be primary pancreatic cancer, locally advanced pancreatic cancer, unresectable pancreatic cancer, metastatic pancreatic cancer, refractory pancreatic cancer, and/or cancer drug resistant pancreatic cancer.
All uses disclosed throughout this application, including but not limited to dosage and dosing regimens, combinations, routes of administration, and biomarkers, can be used to treat pancreatic cancer. In one embodiment, the canarginoumab is administered at a dose of 200mg to 450mg per treatment, wherein the canarginoumab is preferably administered every 3 weeks or preferably every month. In one embodiment, the canargiunumab is administered at a dose of 200mg every 3 weeks or every 4 weeks, preferably subcutaneously. In one embodiment, gavoglizumab is administered at a dose of 90mg to 200mg per treatment, with gavoglizumab administered preferably every 3 weeks or preferably monthly. In one embodiment, the gavojizumab is administered at a dose of 120mg every 3 weeks or month, preferably intravenously.
In one embodiment, the present invention provides gavoglizumab or a functional fragment thereof for use in the treatment of pancreatic cancer, wherein gavoglizumab or a functional fragment thereof is administered in combination with one or more therapeutic agents, e.g., a chemotherapeutic agent. In one embodiment, the therapeutic agent, e.g., chemotherapeutic agent, is a pancreatic cancer standard of care agent. In one embodiment, the one or more therapeutic agents, e.g., chemotherapeutic agents, are selected from albumin-bound paclitaxel (paclitaxel albumin stabilization)The nanoparticle formulation of (4);
In one embodiment, the one or more therapeutic agents are checkpoint inhibitors, wherein PD-1 or PD-L1 inhibitors are preferred, wherein preferably selected from the group consisting of: nivolumab, lanolizumab, altritlizumab, aviluzumab, dolvacizumab, and sibatuzumab (PDR-001).
In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to prevent the recurrence or recurrence of pancreatic cancer in a patient after the cancer has been surgically resected. In one embodiment, the gemtuzumab ozogamicin or a functional fragment thereof is used alone or preferably in combination in the first line treatment of pancreatic cancer. In one embodiment, the gavoglizumab or functional fragment thereof is used alone or preferably in combination in the second or third line treatment of pancreatic cancer. In one embodiment, gavoglizumab or a functional fragment thereof is used alone or, preferably, in combination to treat metastatic pancreatic cancer.
The embodiments disclosed above with respect to gavojizumab or a functional fragment thereof apply to canajirimumab or a functional fragment thereof.
In one aspect, the invention provides a pharmaceutical composition comprising an IL-1 β binding antibody or functional fragment thereof and at least one pharmaceutically acceptable carrier for treating and/or preventing cancer having at least a partial basis for inflammation, including lung cancer, in a patient preferably the pharmaceutical composition comprises a therapeutically effective amount of an IL-1 β binding antibody or functional fragment thereof.
In one aspect of the invention, the canargiunumab, or a functional fragment thereof, is administered intravenously. In one aspect of the invention, the canargiunumab, or a functional fragment thereof, is preferably administered subcutaneously. Unless in the examples in which the route of administration is specified, both routes of administration are applicable to each of the canarginoumab-related examples disclosed herein.
In one aspect of the invention, the gavoglizumab or functional fragment thereof is administered subcutaneously. In one aspect of the invention, the gemfibrozumab or functional fragment thereof is preferably administered intravenously. Unless in the examples in which the route of administration is specified, both routes of administration are applicable to each of the grivoglizumab-related examples disclosed herein.
The canarginoumab can be administered in a reconstituted formulation comprising canarginoumab at a concentration of 50-200mg/ml, 50-300mM sucrose, 10-50mM histidine, and 0.01% -0.1% surfactant, wherein the pH of the formulation is 5.5-7.0. The canarginoumab can be administered in a reconstituted formulation comprising canarginoumab at a concentration of 50-200mg/ml, 270mM sucrose, 30mM histidine, and 0.06
The canarginoumab may also be administered in the form of a liquid formulation comprising 50-200mg/ml concentration of canarginoumab, a buffer system selected from the group consisting of citrate, histidine and sodium succinate, a stabilizer selected from the group consisting of sucrose, mannitol, sorbitol, arginine hydrochloride and a surfactant, wherein the pH of the formulation is 5.5-7.0. The canarginoumab can also be administered in the form of a liquid formulation comprising 50-200mg/ml concentration of canarginoumab, 50-300mM mannitol, 10-50mM histidine and 0.01% -0.1% surfactant, wherein the pH of the formulation is 5.5-7.0. The canarginoumab can also be administered in the form of a liquid formulation comprising 50-200mg/ml concentration of canarginoumab, 270mM mannitol, 20mM histidine, and 0.04
When administered subcutaneously, canargizumab can be administered to a patient in liquid form pre-filled in a syringe or lyophilized for reconstitution.
In one aspect, the invention provides a highly sensitive C-reactive protein (hsCRP), a biomarker for treating and/or preventing cancer (e.g., cancer with at least a partial basis for inflammation, including but not limited to lung cancer) with an inhibitor of IL-1 β (e.g., IL-1 β binding antibody or functional fragment thereof). cancers that typically have at least a partial basis for inflammation include, but are not limited to, lung cancer, particularly NSCLC, colorectal cancer, melanoma, gastric cancer (including esophageal cancer), Renal Cell Cancer (RCC), breast cancer, hepatocellular carcinoma (HCC), prostate cancer, bladder cancer, AML, multiple myeloma, and pancreatic cancer. consistent with previous work indicating that certain cancers have a strong inflammatory component, in humans diagnosed with lung cancer during follow-up, the level of hscnos in the cants test population is higher at baseline than the level of hsCRP in humans not diagnosed with any cancer (6.0 compared to 4.2mg/L, P < 0.001.) and thus, the crp level may be treated with a patient with a definitive lung cancer diagnosis, or a patient who is at risk of using an antibody that binds to IL-1-3976, preferably, or a fragment thereof that binds to IL-1-387, or a functional fragment thereof.
Thus, the present invention provides a high sensitivity C-reactive protein (hsCRP) for the treatment and/or prevention of a biomarker in a cancer with at least a partial basis for inflammation (including lung cancer) in a patient with an action IL-1 β inhibitor, IL-1 β binding antibody or functional fragment thereof, wherein if the level of high sensitivity C-reactive protein (hsCRP) is equal to or higher than 2mg/L, or equal to or higher than 3mg/L, or equal to or higher than 4mg/L, or equal to or higher than 5mg/L, or equal to or higher than 6mg/L, equal to or higher than 7mg/L, equal to or higher than 8mg/L, equal to or higher than 9mg/L, or equal to or higher than 10mg/L, equal to or higher than 12mg/L, equal to or higher than 15mg/L, equal to or higher than 20mg/L or equal to or higher than 25mg/L, as assessed prior to the administration of IL-1 β binding antibody or functional fragment thereof, said patient meeting the conditions in one embodiment, preferably said level of high sensitivity C-reactive protein (hsCRP) is equal to or higher than 6mg/L, preferably higher than the level of hsCRP.
When analyzing the combination dose of canargimab, the lung cancer risk ratio observed in humans achieving a hsCRP reduction greater than the 1.8mg/L median at 3 months was 0.29 (95% CI 0.17-0.51, P <0.0001) compared to placebo, which is superior to those observed effects of hsCRP reduction less than the median (HR 0.83, 95% CI 0.56-1.22, P ═ 0.34).
Thus, in one aspect, the invention relates to the use of a decreased degree of hsCRP as a prognostic biomarker to instruct a physician to continue or discontinue treatment with an IL-1 β inhibitor, an IL-1 β binding antibody or a functional fragment thereof (particularly canargizumab or gavaglizumab), in one embodiment, the invention provides use of an IL-1 β inhibitor, an IL-1 β binding antibody or a functional fragment thereof in the treatment and/or prevention of a cancer having at least a partial basis for inflammation, including lung cancer, wherein the crp level decreases by at least 0.8mg/L, at least 1mg/L, at least 1.2mg/L, at least 1.4mg/L, at least 1.6mg/L, at least 1.8mg/L, at least 3mg/L or at least 4mg/L when the crp level is at least 3 months after the initial IL-1 β binding antibody or a functional fragment thereof is administered for the first time, preferably 3 months, the first time, the IL-1 358 mg/L, at least 1.8mg/L, at least 3mg/L or at least 4mg/L, or less than 200 mg/L, wherein the antibody is administered at a dose less than 200 mg/L, preferably at least 200 mg/L, or less than 200 mg/L, wherein the initial IL-1 g-1.8 mg/L is administered at a dose of a functional fragment of IL-1, preferably at least 200 mg/L, or a functional fragment, preferably at least 200 mg/L, wherein the initial IL-1 g/L, or a three months after the initial IL-1 month, or a functional fragment thereof, preferably at least a month, or a functional fragment thereof, preferably at a month after the initial IL-1 month, or a monthly dose of a functional fragment of a daily administration of IL-1, or a daily administration of a functional fragment of a daily administration of a therapeutic or a functional fragment of an IL-1-150 mg/L, or a daily antibody or a daily administration of a daily antibody or a daily antibody.
In one aspect, the invention provides use of a reduced hsCRP level as a prognostic biomarker to instruct a physician to continue or discontinue treatment of IL-1 β binding antibodies or functional fragments thereof (particularly, canargizumab or gavaguzumab). in one embodiment, when hsCRP levels are reduced to less than 10mg/L, to less than 8mg/L, to less than 5mg/L, to less than 3.5mg/L, to less than 3mg/L, to less than 2.3mg/L, to less than 2mg/L, or to less than 1.8mg/L when IL-1 β binding antibodies or functional fragments thereof are first administered for at least three months, continue such treatment and/or prevention with IL-1 β binding antibodies or functional fragments thereof, in one embodiment, when hsCRP levels are not reduced to less than 3.5mg/L, to less than 3mg/L, to less than 2.3mg/L, to less than 2.5 mg/L, to less than 3mg/L, to less than 300 mg/L when IL-1 3634 binding antibodies or functional fragments are first administered for at least three months, in another embodiment, the second embodiment, the antibody is administered once every month, or twice a month, wherein the antibody is administered at a dose of vacizumab, or at less than 200 mg/300 mg/L, or twice per month, and wherein the antibody is administered once per month, or twice a month, or three months, preferably 200 mg/300 mg/month, or three months, a month, or three months, a month, where the antibody or a month.
In one aspect, the invention provides an IL-1 β binding antibody or a functional fragment thereof for use in treating a cancer having at least a partial basis for inflammation in a patient in need thereof, wherein the IL-1 β binding antibody or functional fragment thereof is administered in a dose sufficient to inhibit angiogenesis in the patient without wishing to be bound by theory, it is hypothesized that inhibition of the IL-1 β pathway results in inhibition or reduction of angiogenesis, which is a critical event for tumor growth and tumor metastasis.
In one embodiment, the cancer is lung cancer, particularly NSCLC. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is renal cancer. In one embodiment, the cancer is melanoma.
In one embodiment, the dose sufficient to inhibit angiogenesis comprises a range of about 30mg to about 750mg, alternatively 100mg-600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg, preferably 150mg to 300mg per treatment, alternatively at least 150mg, at least 180mg, at least 250mg, at least 300mg per treatment of a IL-1 β binding antibody or functional fragment thereof to be administered in one embodiment, a patient having a cancer (including lung cancer) with at least a partial basis for inflammation receives treatment once every 2 weeks, three weeks, four weeks (monthly), 6 weeks, two months (every 2 months), or quarterly (every 3 months).
In one embodiment, the IL-1 β binding antibody is a canargizumab administered at a dose sufficient to inhibit angiogenesis, wherein the dose range is about 100mg to about 750mg, alternatively 100mg to 600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg per treatment, alternatively at least 150mg, at least 200mg, at least 250mg, at least 300mg per treatment in one embodiment, a patient having a cancer (including lung cancer) with at least a partial basis of inflammation receives a treatment every 2 weeks, every 3 weeks, every 4 weeks (monthly), every 6 weeks, every two months (every 2 months) or quarterly (every 3 months).
In one embodiment, the IL-1 β binding antibody is gavozezumab administered at a dose sufficient to inhibit angiogenesis, wherein the dose ranges from about 30mg to about 450mg per treatment, alternatively 90mg-450mg, 90mg to 360mg, 90mg to 270mg, 90mg to 180mg, alternatively 120mg-450mg, 120mg to 360mg, 120mg to 270mg, 120mg to 180mg, alternatively 150mg-450mg, 150mg to 360mg, 150mg to 270mg, 150mg to 180mg, alternatively 180mg-450mg, 180mg to 360mg, 180mg to 270mg, alternatively at least 150mg, at least 180mg, at least 240mg per treatment, at least 270mg, in one embodiment, a patient having a basis of at least partial inflammation including lung cancer receives treatment once every 2 weeks, every 3 weeks, every month, every 6 weeks, every two months (every 2 months) or once a quarter (every 3 months), preferably once every 180mg to 90mg, preferably once every 180mg, 180mg to 180mg, preferably every 180mg, 180mg to 180mg, or 180mg, preferably every 180mg, or 180mg, preferably 180mg, or 180mg, in one embodiment, or 180mg, preferably in one embodiment, a patient having a monthly in one embodiment, wherein the patient having a monthly.
In a preferred embodiment, the IL-1 β antibody or functional fragment thereof is used in combination with one or more chemotherapeutic agents, wherein the chemotherapeutic agent is an anti-Wnt inhibitor, preferably, myristyl mab.
Without wishing to be bound by theory, it is hypothesized that inhibition of the IL-1 β pathway may lead to inhibition or reduction of tumor metastasis no report has been made to date regarding the effect of canarginous on metastasis the data shown in example 3 suggests that IL-1 β activates different pro-metastatic mechanisms at the primary site compared to the metastatic site, with endogenous production of IL-1 β by breast cancer cells promoting epithelial to mesenchymal transition (EMT), invasion, migration and organ-specific homing, once tumor cells reach the bone environment, contact between tumor cells and osteoblasts or bone marrow cells increases IL-1 β secretion by all three cell types, these high concentrations of IL-1 β cause proliferation of bone metastasis microenvironments by stimulating the growth of spreading tumor cells to overt metastases, these anti-metastatic processes can be inhibited by administration of anti-IL-1 β therapy (e.g. canarginou).
Thus, targeting IL-1 β with IL-1 β binding antibodies represents a new therapeutic approach to prevent cancer patients at risk for developing metastases by preventing newly metastasized tumors from seeding from established tumors and keeping tumor cells that have spread into bone dormant.
Accordingly, in one aspect, the invention provides an IL-1 β binding antibody, or a functional fragment thereof, for use in treating a cancer having at least a partial basis for inflammation in a patient in need thereof, wherein the IL-1 β binding antibody, or functional fragment thereof, is administered in a dose sufficient to inhibit metastasis in the patient.
In one embodiment, the dose sufficient to inhibit metastasis comprises the range of about 30mg to about 750mg, alternatively 100mg-600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg, preferably 150mg to 300mg per treatment, alternatively at least 150mg, at least 180mg, at least 250mg, at least 300mg per treatment of a IL-1 β binding antibody or functional fragment thereof to be administered in one embodiment, a patient having a cancer with at least a partial basis of inflammation (including lung cancer) is treated once every 2 weeks, three weeks, four weeks (monthly), 6 weeks, two months (every 2 months), or quarterly (every 3 months).
In one embodiment, the IL-1 β binding antibody is a canargiunumab administered at a dose sufficient to inhibit metastasis, wherein the dose range is about 100mg to about 750mg, alternatively 100mg to 600mg, 100mg to 450mg, 100mg to 300mg, alternatively 150mg-600mg, 150mg to 450mg, 150mg to 300mg per treatment, alternatively at least 150mg, at least 200mg, at least 250mg, at least 300mg per treatment in one embodiment, a patient having a cancer (including lung cancer) with at least a partial basis of inflammation receives treatment every 2 weeks, every 3 weeks, every 4 weeks (monthly), every 6 weeks, every two months (every 2 months), or quarterly (every 3 months).
In one embodiment, the IL-1 β binding antibody is gavozezumab administered at a dose sufficient to inhibit metastasis, wherein the dose ranges from about 30mg to about 450mg per treatment, alternatively 90mg to 450mg, 90mg to 360mg, 90mg to 270mg, alternatively 120mg to 450mg, 120mg to 360mg, 120mg to 270mg, 120mg to 180mg, alternatively 150mg to 450mg, 150mg to 360mg, 150mg to 270mg, 150mg to 180mg, alternatively 180mg to 450mg, 180mg to 360mg, 180mg to 270mg, alternatively at least 150mg, at least 180mg, at least 240mg, at least 270mg per treatment, in one embodiment, a patient with a basis of at least partial inflammation comprises lung cancer is treated every 2 weeks, every 3 weeks, monthly, 6 weeks, every two months (every 2 months) or quarterly (every 3 months), preferably one patient with a cancer having at least partial basis of inflammation, preferably one patient with a cancer, preferably from about 180mg to 90mg, 180mg to 180mg, or 180mg, preferably one patient per month, in one embodiment, 180mg per month, a patient with a monthly, preferably in one patient with a monthly, a monthly schedule, a monthly, a patient having a cancer, a cancer with a cancer having a partial basis of lung cancer, a cancer, 90mg, a monthly, preferably in one patient with a monthly, a patient with a monthly, a patient with a monthly, a patient with a monthly, a monthly.
In one aspect, the invention provides an IL-1 β binding antibody or a functional fragment thereof, preferably gavojizumab or a functional fragment thereof, for use in treating cancer in a patient, wherein the hsCRP level has been reduced to at least 30%, preferably at least 40%, preferably at least 50% compared to baseline (before treatment) or to less than 10mg/L, less than 7mg/L or less than 5mg/L at 6 months or 3 months or 1 month after the first administration of a medicament of the invention, preferably 200mg to 450mg, preferably 200mg, preferably subcutaneous administration every 3 weeks or 4 weeks.
In a preferred embodiment, the IL-1 β antibody or functional fragment thereof is used in combination with one or more chemotherapeutic agents, wherein the chemotherapeutic agent is an anti-Wnt inhibitor, preferably, myristyl mab.
IL-1 β is known to drive gene expression that induces a variety of proinflammatory cytokines, such as IL-6 and TNF- α in the CANTOS assay, administration of canargizumab was observed to be associated with a dose-dependent reduction in IL-6 of 25% to 43% (all P values)<0.0001). Accordingly, the present application provides IL-6 inhibitors for the treatment and/or prevention of cancers having at least a partial basis for inflammation, including but not limited to lung cancer. In some embodiments, the IL-6 inhibitor is selected from the group consisting of: antisense oligonucleotides directed against IL-6, IL-6 antibodies (e.g., cetuximab)
In one aspect, the present application provides a combination of an IL-6 inhibitor and one or more chemotherapeutic agents for use in treating a cancer having at least a partial basis for inflammation. In one embodiment, the one or more chemotherapeutic agents are checkpoint inhibitors. In one embodiment, the checkpoint inhibitor is a PD-1 or PD-L1 inhibitor, preferably selected from the group consisting of: nivolumab, lanolingzumab, alemtuzumab, dulvolumab, avizumab and sibatuzumab (PDR-001).
In one embodiment, the one or more chemotherapeutic agents is a standard of care chemotherapy for a defined cancer having at least a partial basis for inflammation, wherein the cancer is preferably selected from lung cancer, especially NSCLC, colorectal cancer, melanoma, gastric cancer (including esophageal cancer), Renal Cell Carcinoma (RCC), breast cancer, hepatocellular carcinoma (HCC), prostate cancer, bladder cancer, AML, multiple myeloma and pancreatic cancer.
As used herein, canarginoumab is defined under INN number 8836 and has the following sequence:
light chain
Heavy chain:
as used herein, gemfibrolizumab defined under INN number 9310 has the following sequence
Heavy chain-
Light chain-
As used herein, an antibody refers to an antibody that has a native biological form of the antibody. This antibody is a glycoprotein, consisting of four polypeptides (two identical heavy chains and two identical light chains) linked to form a "Y" shaped molecule. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4, depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region CL having one domain. Papain, a proteolytic enzyme, splits the "Y" into three separate molecules, two of which are called "Fab" fragments (Fab ═ fragment antigen binding) and the other "Fc" fragment (Fc ═ crystallizable fragment). The Fab fragment consists of the entire light chain and part of the heavy chain. The VL and VH domains are located at the ends of the "Y" shaped antibody molecule. VL and VH have three Complementarity Determining Regions (CDRs), respectively.
"IL-1 β binding antibody" refers to any antibody that is capable of specifically binding to IL-1 β and thereby inhibiting or modulating the binding of IL-1 β to its receptor and thereby inhibiting the function of IL-1 β preferably, IL-1 β binding antibody does not bind to IL-1 α.
Preferably, the IL-1 β -binding antibody comprises:
(1) an antibody comprising three VL CDRs having the amino acid sequence RASQSIGSSLH (SEQ ID NO:1), ASQSFS (SEQ ID NO:2) and HQSSSSLP (SEQ ID NO:3)) and three VH CDRs having the amino acid sequences VYGMN (SEQ ID NO:5), IIWYDGDNQYYADSVKG (SEQ ID NO:6) and DLRTGP (SEQ ID NO: 7));
(2) an antibody comprising three VL CDRs having the amino acid sequences RASQDISNYLS (SEQ ID NO:9), YTSKLHS (SEQ ID NO:10) and LQGKMLPWT (SEQ ID NO:11)) and three VH CDRs having the amino acid sequences TSGMGVG (SEQ ID NO:13), HIWWDGDESYNPSLK (SEQ ID NO:14) and NRYDPPWFVD (SEQ ID NO: 15)); and
(3) an antibody comprising six CDRs as described in (1) or (2), wherein one or more CDR sequences, preferably at most two CDRs, preferably only one CDR differs from the corresponding sequence described in (1) or (2) by one amino acid, respectively.
Preferably, the IL-1 β -binding antibody comprises:
(1) an antibody comprising three VL CDRs having amino acid sequence RASQSIGSSLH (SEQ ID NO:1), ASQSFS (SEQ ID NO:2) and HQSSLSP (SEQ ID NO:3) and comprising a VH having the amino acid sequence shown in SEQ ID NO: 8;
(2) an antibody comprising a VL having an amino acid sequence shown in SEQ ID NO:4 and comprising three VH CDRs having the amino acid sequences VYGMN (SEQ ID NO:5), IIWYDGDNQYYADSVKG (SEQ ID NO:6) and DLRTGP (SEQ ID NO: 7));
(3) an antibody comprising three VL CDRs having amino acid sequence RASQDISNYLS (SEQ ID NO:9), YTSKLHS (SEQ ID NO:10) and LQGKMLPWT (SEQ ID NO:11) and comprising a VH having the amino acid sequence shown in SEQ ID NO: 16;
(4) an antibody comprising a VL having the amino acids set forth in SEQ ID NO:12 and comprising three VH CDRs having the amino acid sequences TSGMGVG (SEQ ID NO:13), HIWWDGDESYNPSLK (SEQ ID NO:14) and NRYDPPWFVD (SEQ ID NO: 15));
(5) an antibody comprising three VL CDR and VH sequences as described in (1) or (3), wherein one or more VL CDR sequences, preferably at most two CDRs, preferably only one CDR differs by one amino acid from the corresponding sequence described in (1) or (3), respectively, and wherein the VH sequence is at least 90% identical to the corresponding sequence described in (1) or (3), respectively; and
(6) an antibody comprising a VL sequence and three VH CDRs as described in (2) or (4), wherein the VL sequence is at least 90% identical to the corresponding sequence described in (2) or (4), respectively, and wherein one or more of the VH CDR sequences, preferably at most two CDRs, preferably only one CDR, differs from the corresponding sequence described in (2) or (4), respectively, by one amino acid.
Preferably, the IL-1 β -binding antibody comprises:
(1) an antibody comprising a VL having the amino acid sequence shown in SEQ ID NO. 4 and comprising a VH having the amino acid sequence shown in SEQ ID NO. 8;
(2) an antibody comprising a VL having amino acid sequence shown as SEQ ID NO. 12 and comprising a VH having amino acid sequence shown as SEQ ID NO. 16; and
(3) the antibody of (1) or (2), wherein the constant region of the heavy chain, the constant region of the light chain, or both have been changed to a different isotype as compared to canargizumab or gavagizumab.
Preferably, the IL-1 β -binding antibody comprises:
(1) canagalnitumumab (SEQ ID NOS: 17 and 18); and
(2) gevojizumab (SEQ ID NOS: 19 and 20).
The IL-1 β binding antibody as defined above has CDR sequences that are substantially identical or identical to the CDR sequences of canargizumab or gavaglizumab therefore, it binds to the same epitope on IL-1 β and has a similar binding affinity as canargizumab or gavaglizumab.
Additionally or alternatively, the IL-1 β antibody refers to an antibody capable of specifically binding IL-1 β with a similar affinity as canargizumab or gavaglizumab, the Kd of canargizumab in WO 2007/050607 is referenced to 30.5pM and the Kd of gavaglizumab is 0.3 pM. so affinity in the similar range refers to about 0.05pM to 300pM, preferably 0.1pM to 100 pM., although both bind to IL-1 β, canargizumab directly inhibits binding to the IL-1 receptor and gavaglizumab is an allosteric inhibitor that does not prevent IL-1 β from binding to the receptor but prevents receptor activation.
As used herein, the term "functional fragment" of an antibody refers to a portion or fragment of an antibody that retains the ability to specifically bind an antigen (e.g., IL-1 β. examples of binding fragments encompassed within the term "functional fragment" of an antibody include single chain fv (scFv), Fab fragments, which consist of VL、VHA monovalent fragment consisting of the CL and CH1 domains; a f (ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; fd fragment consisting of VHAnd a CH1 domain; fv fragment consisting of a V of one arm of an antibodyLAnd VHDomain composition; dAb fragments (Ward et al, 1989) consisting of VHDomain composition; and an isolated Complementarity Determining Region (CDR); and one or more CDRs arranged on a peptide scaffold, which may be smaller, larger, or differently folded compared to a typical antibody.
The term "functional fragment" may also refer to one of the following:
bispecific single chain Fv dimer (PCT/US 92/09965)
"diabodies" or "triabodies", multivalent or multispecific fragments, which are constructed by gene fusion (TomlinsonI & Hollinger P (2000) Methods Enzymol [ Methods of enzymology ].326: 461-79; W094113804; Holliger P et al, (1993) Proc. Natl. Acad. Sci [ Proc. Natl. Acad. Sci. [ Proc. Acad. Sci.USA, 90:6444-48)
Genetic fusion of scFv to the same or different antibodies (Coloma MJ and Morrison SL (1997) Nature Biotechnology [ Nature Biotechnology ],15(2):159-
scFv, diabody or domain antibody fused to an Fc region
scFv fused to the same or a different antibody
Fv, scFv or diabody molecules can be stabilized by incorporation of a disulfide bridge connecting the VH and VL domains (Reiter, Y. et al, (1996) Nature Biotech [ Nature Biotechnology ],14, 1239-1245).
Small antibodies comprising scFv linked to the CH3 domain can also be prepared (Hu, S. et al, (1996) cancer Res. [ cancer research ],56, 3055-3061).
Other approaches to fragment binding are Fab ' (which differs from Fab fragments by the addition of residues at the carboxy terminus of the heavy chain CH1 structural domain, including one or more cysteines from the antibody hinge region), and Fab ' -SH (which is a Fab ' fragment in which one or more cysteine residues of the constant domain carry a free thiol group).
Typically and preferably, a functional fragment of an IL-1 β -binding antibody is a portion or fragment of "IL-1 β -binding antibody" as defined above.
Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
The following examples illustrate the above invention; however, these examples are not intended to limit the scope of the present invention in any way.
Examples of the invention
The following examples are intended to aid in the understanding of the present invention, but are not intended to, and should not be construed to, limit its scope in any way.
Example 1
A phase III, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of canargiunumab as compared to placebo as an adjunct therapy in adult subjects with completely resected (R0) small cell lung cancer (NSCLC) at stages II-IIIA and IIIB (T >5cm N2)
The objective of this prospective, multicenter, randomized, double-blind, placebo-controlled phase III study was to evaluate the efficacy and safety of canarginoumab as an adjuvant therapy following standard care for fully resected (R0) AJCC/UICC v.8ii-IIIA and IIIB (T >5cm N2) NSCLC subjects.
Design of research
This phase III study CACZ885T2301 adult subjects with completely resected (R0) NSCLC AJCC/UICC v.8II-IIIA and stage IIIB (T >5cm and N2) disease will be enrolled. Prior to screening or randomized cohort for this study, subjects will complete their standard-of-care adjuvant therapy for NSCLC, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Screening can be performed, if possible, after complete surgical resection of NSCLC and confirmation of R0 status (negative pathology), after completion of cisplatin-based dual adjuvant chemotherapy (and radiation therapy for stage IIIA N2 or IIIB N2 disease, if applicable) and compliance with all entry criteria. The subject should not receive prior neoadjuvant chemotherapy or radiation therapy to achieve the R0 state. Approximately 1500 subjects were randomly assigned a 1:1 ratio to canargizumab or matched placebo.
Dosing regimens
This study was double blind. All eligible subjects will be randomly assigned a 1:1 ratio to
One of two treatment groups:
canarginoumab 200mg s.c., 18 cycles on day 1 of every 21-day cycle
Placebo s.c. 18 cycles on day 1 of each 21-day cycle
Randomization will be layered by AJCC/UICC v.8: t >5cm N2 disease IIA compared to IIB compared to IIIA compared to IIIB; histology: squamous and non-squamous; and region: western europe and north america compared to east asia compared to other regions of the world (RoW). The subject will continue with their assigned treatment until 18 cycles are completed or either: recurrence of disease, unacceptable toxicity (failure to further treatment), discretion of the investigator or subject to discontinue treatment, or death or blindness, whichever occurs first. It is speculated that a one year adjuvant therapy will provide acceptable benefit to subjects with moderate or high risk of disease recurrence. If no disease recurrence is observed during the treatment period, subjects will be followed until disease recurrence, subject withdrawal consent, subject interview loss, death, or sponsor termination of the study for up to five years. All subjects who discontinued study treatment will be followed up for survival every 12 weeks until final Overall Survival (OS) analysis or death, loss of access, or withdrawal of consent for follow-up for survival.
Standard care included complete resection of NSCLC with no cancer at the margins. All subjects with stage IIB-IIIA and IIIB (T >5cm N2) disease require four cycles of cisplatin-based duplex chemotherapy (unless intolerant, in which case at least two cycles of adjuvant chemotherapy are required); chemotherapy is recommended, but not necessary, for patients with stage IIA T (>4-5 cm). Radiation therapy is suggested for the mediastinal lymph nodes, but not all subjects with stage IIIA N2 and IIIB (T >5cm N2) disease require radiation therapy. All subjects had to have a complete surgical resection of their NSCLC to be eligible for study; the margin must be pathologically examined and recorded as negative. The efficacy between the two groups will be compared: DFS, OS, LCSS and quality of life metrics (EQ-5D-5L and EORTC QLQ-C30/LC13) and a comparison of safety.
Detection of the first disease recurrence will be accomplished by clinical evaluation, including physical examination and investigator-determined radiation tumor measurements. If there is no definitive radiological evidence, a biopsy should be taken to confirm the recurrence. The following evaluations were required at screening/baseline: if clinically needed, CT or MRI, brain MRI and whole-body bone scan of the chest, abdomen and pelvis are requested. Subsequent imaging assessments were performed every 12 weeks (+ -7 days) in the first year (treatment phase) after day 1 of cycle 1, then every 26 weeks in the second and third years, and every year in the fourth and fifth years (post-treatment monitoring). As noted above, whether study treatment is suspended temporarily or permanently, or whether an unplanned assessment is performed, prior to the last scheduled dose administration on day 1 of the 18 th cycle, the intervals between imaging assessments for all study phases as described above should be respected. If subjects discontinue study treatment for reasons other than relapse, relapse assessment should continue on the scheduled visit until disease relapse, subject withdrawal consent, subject missed visit, death, or sponsor termination of study.
Primary and critical secondary objectives:
main object of
The primary objective was to compare disease-free survival (DFS) in cana's geminumab versus placebo as assessed by local researchers.
Statistical assumptions, models, and methods of analysis
Assuming a proportional hazards model for DFS, the following statistical assumptions will
Tested to address the main efficacy goals:
h01 (invalid hypothesis): Θ 1 ≧ 0 in comparison to Ha1 (alternative hypothesis): theta 1<0
Where Θ 1 is the logarithm of DFS in the Carnaginumumab (study) group compared to the placebo (control) group
Hazard ratio.
The primary efficacy analysis to test this hypothesis and compare the two treatment groups would include a tiered log rank test with an overall significance level of 2.5%. The layering will be based on the following random layering factors: AJCC/UICC v.8IIA stage of T >5cm N2 disease is compared with IIB stage and IIIA stage and IIIB stage; histology: squamous and non-squamous; and region: western europe and north america compared to east asia compared to other regions of the world (RoW). The hazard ratio of DFS and its 95% confidence interval will be calculated from the layered Cox model using the same layering factors as the log rank test.
Key secondary objectives
A key secondary objective was to determine whether canarginoumab treatment could prolong overall survival OS compared to placebo. The OS is defined as the time from the randomized date to death of any cause. If it is not known that a subject has died, OS is assigned to the latest date (expiration date or prior) on which the subject is known to be alive. Assuming a proportional hazards model for OS, the following statistical assumptions are tested only if DFS is statistically significant:
h02 (invalid hypothesis):
Where
OS distribution will be estimated using the Kaplan-Meier method and the Kaplan-Meier curve, median and 95% confidence interval for the median will be provided for each treatment group. The hazard ratio of OS and its 95% confidence interval will be calculated using the hierarchical Cox model.
Secondary target
1. Comparing lung cancer specific survival in canarginoumab group compared to placebo group:
lung cancer specific survival (lcs) is defined as the time from the date of randomization to the date of death due to lung cancer. Analysis will be performed based on FAS populations according to the random treatment groups and the hierarchy assigned to the random groupings. The LCSS distribution will be estimated using the Kaplan-Meier method and the Kaplan-Meier curve, median and 95% confidence interval for the median will be provided for each treatment group. The hazard ratio for LCSS and its 95% confidence interval will be calculated using the layered Cox model.
2. Characterization of the safety of Kanagilnuumab
Frequency of adverse events, ECG and laboratory abnormalities
3. Characterization of pharmacokinetics of Kanagilnuumab therapy
Serum concentration-time profiles of canargiunumab and appropriate individual PK parameters based on population PK model
4. Characterization of incidence and incidence of immunogenicity of Kanagilu monoclonal antibodies (anti-drug antibodies, ADA)
Serum concentration of anti-Kanagilnua monoclonal antibody
5. Evaluation of Caragagenumumab compared to placebo for PRO (EORTC QLQ-C30 and EQ-5D combined with QLQ-LC 13), including function and health-related quality of life
The time to deterministic 10-point worsening symptom scores for pain, cough, and dyspnea were the primary objective PRO variables for each QLQ-LC13 questionnaire. The time to deterioration of overall health/QoL certainty, shortness of breath and pain, and the effects derived from EQ-5D-5L for each QLQ-C30 are secondary PRO variables of interest
The european cancer research and treatment organization's core quality of life questionnaire EORTC-QLQC30 (version 3.0) and its lung cancer specific module QLQLC13 (version 1.0) will be used to collect data on subject function, disease-related symptoms, health-related quality of life and health status. EQ-5D-5L will be used for the purpose of calculating utility that can be used in health economic research. EORTC QLQ-C30/LC13 and EQ-5D-5L are reliable and effective methods often used in clinical trials of lung cancer subjects and were previously used in adjuvant settings (Bezjak et al, 2008).
Example 2A
Blockade of IL-1 β signaling alters blood vessels in the skeletal microenvironment
We have recently identified interleukin-1 β (IL-1 β) as a potential biomarker for predicting an increased risk of bone metastasis in breast cancer patients furthermore, we have shown that blocking IL-1 β activity inhibits bone metastasis in breast cancer cells that spread in the skeleton and reduces tumor angiogenesis we hypothesize that the interaction between IL-1 β and IL-1R also promotes neovascularization in the bone microenvironment that stimulates the development of metastases at this site.
The aim was to investigate the effect of blocking IL-1 β activity on angiogenesis in bone.
Method the effect of IL-1R inhibition on the blood vessels of the trabecular bone was determined in mice treated with IL-1 β antibody Kanagirunumab (Ilaris) for 0-96 hours or in genetically engineered IL-1R1 knock-out (KO) mice at 21/31 days with IL-1R antagonist (anakinra) at 1mg/kg, the blood vessels were observed after immunohistochemistry for CD34 and endoglin, and the concentration of Vascular Endothelial Growth Factor (VEGF) and endothelin-1 in serum and/or bone marrow was determined by ELISA the effect on bone volume was measured by microscopic computerized tomography (uCT).
As a result: canargiunumab (Ilaris) caused a significant decrease in the length of new blood vessels from 0.09mm (control) to 0.06mm (24 h Ilaris) (P ═ 0.0319). IL-1R1 KO mice and mice treated with anakinra showed a decrease in mean length of new blood vessels. Inhibition of IL-1R results in an increase in trabecular bone volume. Anakinra reduced endothelin-1 concentrations by 69% (P ═ 0.0269) and VEGF concentrations by 22% (P ═ 0.0104) in mice treated for 31 days. Kanagilunumab (Ilaris) reduced VEGF concentration by 46% and endothelin-1 concentration by 47% in mice treated for 96 hours.
And (4) conclusion: these data indicate that IL-1R activity plays an important role in the formation of new blood vessels in bone and that pharmacological inhibition of its activity has potential as a new therapy for bone metastasis of breast cancer.
Example 2B
IL-1B signaling regulates breast cancer bone metastasis
Breast cancer bone metastasis is incurable and is associated with poor patient prognosis. After homing and colonizing the bone, breast cancer cells will remain dormant until signals from the microenvironment stimulate these already disseminated cells to proliferate to form significant metastases. We have recently identified
Here, we report findings on the role of IL-1B signaling in breast cancer bone metastasis: using a murine model of spontaneous human breast cancer metastasis to human bone, we found that administration of the clinically useful anti-IL-1B monoclonal antibody Ilaris significantly reduced bone metastasis while increasing primary tumor growth. However, blocking IL1R1 with the recombinant form of the receptor antagonist anakinra delayed the onset of breast cancer metastasis in human bone without affecting the development of primary breast cancer. These findings suggest that IL1 signaling may play a different role at the primary and metastatic sites of breast cancer. Our data further highlights the role of tumor-derived and microenvironment-derived IL-1 signaling in tumor cell spreading and growth in bone: inhibition of IL-1B/IL-1R1 by Ilaris or anakinra reduces bone turnover and neovascularization, making the skeletal microenvironment less suited for breast cancer cell growth. In addition, overexpression of IL1B or IL1R in human breast cancer cells increases bone metastasis by direct injection into circulating tumor cells in the body. These data indicate that IL-1B/IL-1R1 signaling plays an important role in the development of bone metastases, and that pharmacological inhibition of its activity has potential as a new therapy for breast cancer bone metastases.
Example 2C
Targeting IL1b-Wnt signaling may prevent colonization of breast cancer in the bone microenvironment
In breast cancer, the spread of tumor cells to the bone marrow is an early event, but these cells can be dormant in the bone environment for many years before final colonization. Treatment of bone metastases is not curative, so neoadjuvant therapy to prevent disseminated cells from becoming metastatic lesions may be an effective treatment option to improve clinical outcome. There is evidence that Cancer Stem Cells (CSCs) within breast tumors are cells that are capable of metastasizing; however, little is known about which bone marrow derived factors support dormant CSC survival and eventual colonization. Using in vitro cultures of primary human bone marrow and patient-derived breast cancer cells, and in vivo models of metastasis of human breast cancer cells implanted in mice, we investigated signaling pathways that regulate CSC colony formation in bone.
We demonstrate that exposure to the bone microenvironment stimulates breast CSC colony formation in 15/17 patient-derived early breast cancer in vitro and contributes to a 3-4 fold increase in colony formation in intrafemoral injected breast cancer cells in vivo (p/0.05). Furthermore, we confirmed that human bone marrow secreted IL1b induced the formation of mammary CSC colonies by inducing Wnt secreted intracellular NFkB signaling. Importantly, we show that inhibition of IL1b (using IL1b neutralizing antibody or IL1R antagonist anakinra) or Wnt signaling (using pleiotuximab, a therapeutic antibody that binds 5/10 frizzled receptor) both retropotently induces CSC activity in the extramedulla of the body (anakinra; p \0.0001, pleiotitumomab; p \0.01) and prevents spontaneous bone metastasis in vivo (IL1b neutralizing antibody; p \0.02, pleiotitumomab; p \ 0.01). These data suggest that IL-1b-Wnt inhibitors will prevent the formation of metastatic colonies in bone by spreading CSCs and represent an attractive adjunctive therapeutic opportunity in breast cancer. Drugs directed against IL-1b (anakinra and canajirimumab) have been FDA approved for other indications, and anti-Wnt therapy (vantituzumab) is in clinical trials for cancer, making it a useful therapeutic target for breast cancer patients.
Example 2C
Targeting IL-1 β -Wnt signaling to prevent breast cancer
Colonization in bone microenvironment
In breast cancer, the spread of tumor cells into the bone marrow is an early event, but these cells can be dormant in the bone environment for many years before clinical bone metastasis occurs. There is evidence that Cancer Stem Cells (CSCs) within breast tumors are cells that are capable of metastasizing, but the effect of the bone environment on CSC regulation has not been studied. We used two models to study this problem: in vitro culture of Primary human bone marrow and patient-derived Breast cancer cells, and in vivo Intra-femoral injection of luciferase
tdTomato labeled breast cancer cells entered immunodeficient mice. CSC activity after isolation from the bone environment was measured using mammococcal colony formation.
We demonstrate that exposure to bone microenvironment stimulates breast CSC colony formation in 15/17 patient-derived early breast cancer in vitro and promotes a 3-4 fold increase in colony formation in breast cancer cells injected into the femoral bone marrow of mice in vivo (p/0.05). furthermore, we confirm that IL1b secreted by human bone marrow induces breast CSC colony formation by inducing Wnt signaling in breast cancer cells we show that inhibition of IL1 β (using IL1 β neutralizing antibodies or IL1R antagonist anakinosin) or Wnt signaling (using pleiotuximab, a therapeutic antibody that binds 5/10 frizzled receptor), both reverses induction of CSC activity by the bone marrow in vitro (anakinosin; p <0.0001, pleiotitumomab; p <0.01) and prevents spontaneous bone metastasis in vivo (IL1 β neutralizing antibodies; p <0.02, pleiotoman; p < 0.01).
These data indicate that IL-1 β -Wnt inhibitors can prevent the formation of metastatic colonies by spreading CSCs in bone and should therefore be considered as an adjunct treatment opportunity for breast cancer clinically useful drugs against IL-1 β (anakinra and canajirimumab) have been licensed for other applications and anti-Wnt therapy (myrituzumab) is in clinical trials, making this pathway a useful therapeutic target for breast cancer patients.
Example 2D
anti-IL 1B therapy and standard of care agents: double-edged sword for preventing breast cancer bone metastasis
Breast cancer bone metastasis is incurable and is associated with poor patient prognosis. After homing and colonizing the bone, breast cancer cells will remain dormant until signals from the microenvironment stimulate these already disseminated cells to proliferate to form significant metastases. We have recently identified
Here, we report on the IL-1B signaling in breast cancer bone metastasis role discovery. Using a murine model of spontaneous human breast cancer metastasis to human bone, we found that administration of a clinically useful anti-IL-1B monoclonal antibody Ilaris or a clinically useful recombinant form of the receptor antagonist anakinra reduced bone metastasis (photon/second mean: 3.60E +06 placebo, 4.83E +04 anakinra, 6.01E +04 Ilaris). According to this finding, the overexpression of IL-1B or IL-1R1 in human breast cancer cells resulted in enhanced tumor cell proliferation and growth in bone (12.5%, 75% and 50% for animals with bone tumors, IL-1B overexpressing cells and IL-1R overexpressing cells, respectively, in the control group). For patients with breast cancer, the use of standard of care agents and/or anti-resorptive medications is a therapeutic strategy. Here, we used anti-IL 1B therapy (anakinra) in combination with standard of care agents (doxorubicin) and/or anti-resorptive agents (zoledronic acid) in a syngeneic model of breast cancer metastasis. Our experiments showed that triple therapy significantly attenuated breast cancer metastasis (p ═ 0.0084).
Taken together, these data indicate that IL-1B/IL-1R1 signaling plays an important role in the development of bone metastases and has the potential to be a new therapy for bone metastases, either by inhibiting their activity pharmacologically alone or in combination with standard of care therapies.
Example 3
Tumor-derived IL-1 β induces different mechanisms for promoting tumor metastasis
Materials and methods
Cell culture
Human breast cancer MDA-MB-231-Luc 2-TdTimato (Callier Life sciences, Manchester, UK), MDA-MB-231 (parental) MCF7, T47D (European authoritative cell culture Collection (ECACC)), MDA-MB-231-IV (Nutter et al, 2014), and bone marrow HS5(ECACC) and human primary osteoblasts OB1 were cultured in DMEM + 10% FCS (Gibco, Invitrogen, Persley (Paisley, UK). All cell lines were cultured in a humidified incubator at 5% C02 and used at low passage rates > 20.
Tumor cell transfection:
human MDA-MB-231, MCF7 and T47D cells were stably transfected with plasmid DNA purified from competent E.coli (which had been transduced with ORF plasmids containing human IL1B or IL1R1 (accession numbers NM-000576 and NM-0008777.2, respectively) with a C-terminal GFP tag (OriGene technologies Inc., Rokville, Md.) to overexpress gene IL1B or IL1R 1. Using PureLinkTMHipure plasmid miniprep reagentThe cassette (semer feishel (thermofisher)) was used for plasmid DNA purification and DNA quantification by UV spectroscopy, which was then introduced into human cells by means of Lipofectamine II (semer feishel). Control cells were transfected with DNA isolated from the same plasmid without the IL-1B or IL-1R1 coding sequence.
In vitro study
In vitro studies were carried out with or without the addition of 0-5ng/ml of recombinant IL-1 β (R & D systems, Wisbardon, Germany) +/-50. mu.M IL-1Ra (Anne (Amgen), Cambridge, UK).
Cells were transferred to fresh medium containing 10% or 1% FCS. By using 1/400mm2Cell proliferation was monitored by a hemocytometer (Hawkley, lanning UK) by manual cell counting for 120 hours every 24 hours or 72 hours using an xcelligene RTCA DP instrument (ace Biosciences, Inc). Invasion of tumor cells was assessed using a 6mm clear well plate (Corning Inc.) with a pore size of 8 μm with or without a basement membrane (20% Matrigel; invitrogen). Tumor cells were plated at 2.5 × 10 in DMEM + 1% FCS5(for parental and MDA-MB-231 derivatives) and 5x105(for T47D) density into the inner chamber, and will be supplemented with 5% FCS 5x105OB1 osteoblasts were added to the outer chamber. At 24 and 48 hours post-inoculation, cells were removed from the apical surface of the membrane and passed through hematoxylin and eosin (H)&E) Cells that had invaded the wells were stained and then imaged on a Leica DM7900 light microscope and counted manually.
Cell migration was studied by analyzing wound closure: cells were seeded onto 0.2% gelatin in 6-well tissue culture plates (Costar; Corning), and once confluent, mitomycin C was added at 10. mu.g/ml to inhibit cell proliferation and scored 50 μm on a monolayer. The percentage of wound closure was measured at 24 and 48 hours using a CTR7000 inverted microscope and LAS-AF v2.1.1 software (lycra application suite; lycra Microsystems (Leica Microsystems), westerlar, germany). All proliferation, invasion and migration experiments were repeated using an xcelligene RTCA DP instrument and RCTA software (ests biotechnology).
For co-culture studies with human bone, 5x105MDA-MB-231 or T47D cells were seeded onto tissue culture plastic or 0.5cm3Human bone plates for 24 hours medium was removed and the concentration of IL-1 β was analyzed by ELISA for co-culture with HS5 or OB1 cells, 1X105MDA-MB-231 or T47D cells with
Animal(s) production
In the IL-1 β/IL-1R1 overexpression bone homing experiments, 6 to 8 weeks old female BALB/C nude mice were used to study the effect of IL-1 β on the bone microenvironment, 10 weeks old female C57BL/6 mice (Charles River, kente, UK) or IL-1R1 mice were used-/-Mice (Abdulai et al, 2016). Mice were maintained in a 12h light/dark cycle, with free access to food and water. Experiments were conducted with approval from the british department of internal medicine according to
Patient consent and preparation of the pelvic disc
All patients provided written informed consent prior to participation in the study. Human bone samples were collected according to HTA permit 12182 of the musculoskeletal bio-bank, university of sheffield, uk. Trabecular bone cores were prepared from femoral heads of female patients undergoing hip replacement surgery using an Isomat 4000 precision saw (standard instruments) with a precision diamond wafer saw blade (standard instruments (Buehler)). Subsequently, a disc of 5mm diameter was cut using trephine and then stored in sterile PBS at room temperature.
In vivo studies
To mimic the transfer of human breast cancer to a human bone implant, two human bone plates were implanted subcutaneously into 10-week-old female NOD SCID mice (n-10/group) under isoflurane anesthesia. Mice received a 0.003mg injection of vetgessic and Septrin was added to drinking water for 1 week after bone implantation. Mice were left for 4 weeks, thenTwo post-mammary fat pads injected with 1X10 in 20% Martigel/79% PBS/1% toluene blue5MDA-MB-231Luc2-Tdtomato, MCF7 Luc2 or T47D Luc2 cells. The development of primary tumors growth and metastasis was monitored weekly after subcutaneous injection of 30mg/ml D-fluorescein (invitrogen), using the IVIS (luminel) system (Caliper Life Sciences). After the experiment was completed, breast tumors, circulating tumor cells, serum and bone metastases were excised. RNA was processed by real-time PCR for downstream analysis, and cell lysates were used for protein analysis and histological examination of the whole tissue as described previously (Nutter et al, 2014; Ottewell et al, 2014 a).
For therapeutic studies in NOD SCID mice, placebo (control), 1mg/kg IL-1Ra were administered starting 7 days after tumor cell injection(daily) or 10mg/kg of Canatkinumab (subcutaneous every 14 days). In BALB/C mice and C57BL/6 mice, 1mg/kg IL-1Ra was administered daily for 21 or 31 days, or 10mg/kg canajirimumab was administered as a single subcutaneous injection. Tumor cells, serum and bone were subsequently excised for downstream analysis.
Mixing 5x105Bone metastasis was studied after injection of MDA-MB-231GFP (control), MDA-MB-231-IV, MDA-MB-231-IL-1B positive or MDA-MB-231-IL-1R1 positive cells into the lateral tail vein of 6 to 8 week old female BALB/c nude mice (n ═ 12/group). Tumor growth in bones and lungs was monitored weekly in live animals by GFP imaging. Mice were sorted 28 days after tumor cell injection, at which time hind limbs, lungs, and serum were excised and subjected to microcomputerized tomography (μ CT), histology of bone turnover markers and circulating cytokines, and ELISA analysis (Holen et al, 2016).
Isolation of circulating tumor cells
Whole blood was centrifuged at 10,000g for 5 minutes, and then serum was removed for ELISA analysis. The cell pellet was resuspended in 5ml FSM lysis solution (Sigma Aldrich, Pull (Pool), UK) to lyse red blood cells. The remaining cells were re-pelleted, washed 3 times in PBS and resuspended in PBS/10% FCS. Samples of 10 mice per group were collected and TdTimato positive tumor cells were isolated using a MoFlow high efficiency cell sorter (Beckman Coulter, Cambridge, UK) with 470nM laser line from Coherent I-90C permanent argon ion (Coherent, Santa Clara, Calif.). TdTimato fluorescence was detected with a 555LP dichroic long pass and 580/30nm band pass filter. Cell collection and analysis was performed using Summit 4.3 software. Immediately after sorting, the cells were placed in RNA protective cell reagent (Ambion, Persley, Renfree, UK) and stored at-80 ℃ before RNA extraction.
And (3) microcomputer tomography imaging:
a microcomputer tomography (μ CT) analysis was performed using a Skyscan 1172X-ray computer μ CT scanner (Skyscan, Aartsell, Belgium) equipped with an X-ray tube (voltage 49 kV; current 200uA) and a 0.5-mm aluminum filter. The pixel size was set to 5.86 μm, as previously described (Ottewell et al, 2008 a; Ottewell et al, 2008b) scanning from the proximal top of the tibia.
Bone histology and measurement of tumor volume:
bone tumor area was measured on three non-serial, H & E stained, 5 μm decalcified tibial histological sections of each mouse using a leica RMRB upright microscope and an osteorecord software (osteorecords, inc., Decauter, usa) and a computer image analysis system as previously described (Ottewell et al, 2008 a).
Western blotting:
proteins were extracted using a mammalian cell lysis kit (sigma aldrich, Poole, uk). 30 μ g of protein was run on a 4% -15% pre-made polyacrylamide gel (BioRad, Wattford, UK) and then transferred to Immobilon nitrocellulose membrane (Millipore Corp.). Nonspecific binding was blocked with 1% casein (Vector Laboratories), and then incubated with either rabbit anti-human N-cadherin (D4R1H) monoclonal antibody (1:1000 dilution), E-cadherin (24E10) (1:500 dilution) or gamma-catenin (2303) (1:500 dilution) (Cell signalling) or mouse monoclonal GAPDH (ab8245) (1:1000 dilution) (Abcam, Cambridge, UK) for 16 hours at 4 ℃. The secondary antibody was anti-rabbit or anti-mouse horseradish peroxidase (HRP; 1:15,000), and HRP was detected using the Supersignal chemiluminescence detection kit (Pierce). Quantification of bands was performed using Quantity Once software (BioRad) and normalized to GAPDH.
Gene analysis
Total RNA was extracted using RNeasy kit (Qiagen) and reverse transcribed to cDNA using Superscript III (Invitrogen AB). Relative mRNA expression of IL-1B (Hs02786624), IL-1R1(Hs00174097), CASP (caspase 1) (Hs00354836), IL1RN (Hs00893626), JUP (crosslinked zebulin/γ -catenin) (Hs00984034), N-cadherin (Hs01566408), and E-cadherin (Hs1013933) was compared to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH; Hs02786624) and evaluated using the ABI 7900PCR system (Perkin Elmer, Foster City, Calif.) and Taqman Universal premix (Muscae Feishi, UK). Fold changes in gene expression between treatment groups were analyzed by inserting CT values into Data Assist V3.01 software (Applied Biosystems), and only genes with CT values ≦ 25 were analyzed for gene expression changes.
Evaluation of IL-1 β and IL-1R1 in tumors of breast cancer patients
The expression of IL-1 β and IL-1R1 was assessed on a Tissue Microarray (TMA) containing a core of primary breast tumor obtained from 1,300 patients included in the azere clinical trial (Coleman et al, 2011.) samples were taken from patients with stage II and III breast cancer with no signs of metastasis and pre-treated following random patient staining for 10 years with standard adjuvant therapy with or without addition of zoledronic acid (Coleman et al, 2011.) for TMA IL-1 β (ab2105, 1:200 dilution, Abcam corporation) and IL-1R1(ab 995, 1:25 dilution, Abcam corporation) and blinded to IL-1 β/IL-1R1 in tumor cells or associated stroma under the direction of a tissue pathologist, then tumor or IL-1 β or IL-1R1 was linked to disease recurrence (any site) or other sites, particularly within the bone (+ -bone).
The IL-1 β pathway is upregulated during metastasis of human breast cancer to human bone.
Using this model, the expression level of genes associated with the IL-1 β pathway was increased stepwise at each stage of the process of heterometastasis in triple negative (MDA-MB-231) and estrogen receptor positive (ER + ve) (T47D) breast cancer cells, genes associated with the IL-1 β signaling pathway (IL-1B, IL-1R1, CASP (caspase 1) and IL-1Ra) were expressed at very low levels in both MDA-MB-231 and T47D cells in vitro, and the expression of these genes was not altered in primary breast tumors of the same cells that were not metastasized in vivo (FIG. 7 a).
Both IL-1B, IL-1R1 and CASP were significantly increased in breast tumors that subsequently metastasized to human bone (p <0.01 for both cell lines) compared to non-metastatic breast tumors, thereby activating IL-1 β signaling as shown by ELISA against activated 17kD IL-1 β (FIG. 7B; FIG. 8). IL-1B gene expression in circulating tumor cells was increased (p <0.01 for both cell lines) compared to metastatic breast tumors and further increases in tumor cells isolated from human bone metastases, compared to their corresponding breast tumors, IL-1B (p <0.001), IL-1R1(p <0.01), CASP (p <0.001), and IL-1Ra (p <0.01), resulted in further activation of the IL-1 β protein (FIG. 7; FIG. 8). these data indicate that IL-1 β signaling can both promote metastasis from the primary site and also the development of breast cancer in bone metastases.
Tumor-derived IL-1 β promotes EMT and breast cancer metastasis.
In primary tumors metastasizing to bone, the expression levels of genes associated with tumor cell adhesion and epithelial to mesenchymal transition (EMT) were significantly altered compared to non-metastatic tumors (FIG. 7 c). IL-1 β overexpressing cells (MDA-MB-231-IL-1B +, T47D-IL-1B + and MCF7-IL-1B +) were generated to investigate whether tumor-derived IL-1 β is responsible for inducing EMT and metastasis to bone. all IL-1 β + cell lines showed an increase in EMT, showed a morphological change from epithelial to mesenchymal phenotype (FIG. 9a), and decreased expression of E-cadherin and JUP (cross-linked plakoglobin/γ -catenin), increased expression of N-cadherin genes and proteins (FIG. 9B). the expression of N-cadherin genes and proteins (MDA-MB-231-IL-1 + β + p <0.0001 (FIG. 9 d); p < 0.001-1-IL-231-IL-1 + cells were increased in mice recruited to the primary tumor cell line (IL-2 + cells) in vitro) and in the tumor cells were recruited to the same tumor cells in the same period as those of primary tumors found in humans (AZF-2-mediated tumor cells), and tumor-derived IL-1 cells in the primary tumors found to bone-2-derived IL-1-derived from the same tumor-2-derived IL-1 cell recruitment (FIG. 7c) and tumor-mediated tumor-derived IL-mediated tumor-2) and tumor-mediated increase in the same time period of patients (FIG. 7c) as in the tumor-mediated tumor-derived IL-mediated metastasis to bone-derived IL-1 cells in vitro (FIG. 7c) and the tumor-mediated increase in the tumor-mediated increase in the same time period of patients (FIG. 7c) and in mice) and tumor-mediated tumor-derived IL-derived tumor-mediated tumor-derived tumor-mediated tumor-derived IL-mediated tumor-.
Inhibition of IL-1 β signaling reduces spontaneous metastasis of human bone.
Since tumor-derived IL-1 β appears to promote the development of metastasis by inducing EMT, the inhibition of IL-1 β signaling with IL-1Ra (anakinra) or a human anti-IL-1 β binding antibody (canarginoumab) was studied for the effect on spontaneous metastasis to human bone implants that both IL-1Ra and canarginoumab can reduce metastasis to human bone, 7 in 10 control mice detected metastasis to human bone implants, but only 4 in 10 mice treated with IL-1Ra and 1 in 10 mice treated with canarginoumab the number of cells detected in the circulation of the group treated with IL-1Ra and canarginoumab was also less than the number of cells detected in the placebo treated group (FIG. 10 a). the number of cells detected in the circulation of mice treated with canarginoumab or IL-1Ra was significantly less than the number of cells detected in the placebo treated group: the number of cells detected in the mice treated with canarginoulli and/or IL-1Ra, respectively, the number of cells detected in the circulation of cells detected in the mice treated with canarginoumenon or IL-1Ra was significantly less than the number of cells detected in the placebo treated mice with the placebo group (FIG. β, the anti-IL-1A-1 anti-IL-1-trastuzumab, and/7 anti-IL-1-7 binding antibody, thus the effect of inhibiting the tumor metastasis of the tumor cells in the tumor-metastasis of the tumor-metastasis in the tumor-metastasis of the blood (1) was shown by the anti-metastasis of the tumor-metastasis.
Tumor-derived IL-1B promotes homing and colonization of breast cancer cells.
In this study, intravenous injection of MDA-MB-231-IL-1 β + cells into BALB/c nude mice resulted in a significant increase (75%) in the number of animals that developed bone metastasis compared to control cells (12%) (p <0.001) cells (fig. 11a) MDA-MB-231-IL-1 β + tumors caused a significantly greater development of osteolytic lesions in mouse bones (p ═ 0.03; fig. 11b) compared to control cells, and there was a tendency for reduced lung metastasis in mice injected with MDA-MB-231-IL-1 β + cells (p ═ 0.16; fig. 11b) compared to control cells (p ═ 0.16; fig. 11c) and the endogenous tumor metastasis data could be shown to promote in these mice.
The interaction of tumor cells with bone cells further induces IL-1B and promotes the development of significant metastases.
Genetic analysis data from a mouse model of human breast cancer metastasis to a human bone implant showed that the IL-1 β pathway was further increased when breast cancer cells were grown in the bone environment compared to metastatic cells in the primary site or circulation (fig. 7 a.) thus, it was investigated how the production of IL-1 β was altered when tumor cells were in contact with bone cells, and how IL-1 β altered the bone microenvironment to affect tumor growth (fig. 12). culturing human breast cancer cells into a fully human bone segment for 48 hours resulted in increased secretion of IL-1 β into the culture medium (p <0.0001 for MDA-MB-231 and T47D cells; fig. 12 a.) co-culture with human HS5 bone marrow cells showed that IL-1 β concentrations derived from cancer cells (p <0.001) and bone marrow cells (p <0.001) were increased, with approximately 1000-fold increase in IL-1 β derived from tumor cells and approximately 100-fold increase in IL-1B derived from human HS5 cells (fig. 12B).
In contrast, IL-1 β stimulates the proliferation of bone marrow cells, osteoblasts and blood vessels, and thus induces the proliferation of tumor cells (FIG. 11). therefore, the arrival of tumor cells expressing high concentrations of IL-1 β stimulates the expansion of metastatic microenvironment components, and contact between tumor cells expressing IL-1 β and osteoblasts/blood vessels drives tumor colonization of bone.A study of exogenous IL-1 β and IL-1 β from tumor cells on tumor cells, osteoblasts, bone marrow cells and CD34+Effects of vascular proliferation: co-culture of HS5 bone marrow or OB1 primary osteoblasts with breast cancer cells resulted in increased proliferation of all cell types (P for HS5, MDA-MB-231 or T47D<0.001, FIG. 12c) (for OB1, MDA-MB-231 or T47D, P<0.001, fig. 12d) direct contact between tumor cells, primary human bone samples, bone marrow cells or osteoblasts promotes the release of IL-1 β from tumors and bone cells (fig. 12) furthermore, administration of IL-1 β increased the proliferation of HS5 or OB1 cells but not breast cancer cells (fig. 13a and 13b), indicating that the interaction of tumor cells with bone cells promotes the production of IL-1 β, which can drive the expansion of the microenvironment and stimulate the formation of significant metastases.
IL-1 β signaling was also found to have profound effects on bone microvasculature by knocking IL-1R1 out to prevent IL-1 β signaling in bone, pharmacological blockade of IL-1R with IL-1Ra or reduction of circulating concentrations of IL-1 β by administration of the anti-IL-1 β binding antibody Kanagiruzumab reduced the average length of CD34+ vessels in tumor-colonized trabecular bone (for IL-1Ra and Kanagiruzumab treated mice, p<0.01) (FIG. 13c) these findings were confirmed by endorphin staining, which showed a reduced number of vessels in bone and vessel length when IL-1 β signal was disrupted ELISA for endothelinAnalysis of 1 and VEGF showed IL-1R1 compared to control-/-Mouse (p)<0.001 endothelin 1; p is a radical of<0.001VEGF) and with IL-1R antagonists (p)<0.01 of endothelin 1; p is a radical of<0.01VEGF) or Kanagilunumab (p)<0.01 of endothelin 1; p is a radical of<0.001VEGF) were reduced (e.g., 14). these data indicate that increased IL-1 β associated with tumor cell-bone cells and high levels of IL-1 β in tumor cells also promote angiogenesis, further stimulating metastasis.
Tumor-derived IL-1 β predicts future breast cancer recurrence in bone and other organs in patient material
To establish the correlation of clinical findings, the correlation between IL-1 β and its receptor IL-1R1 in patient samples was studied, IL-1R1 or the active form of IL-1 β (17kD) staining was performed on approximately 1300 primary tumor samples from stage II/III breast cancer with no evidence of metastasis (Coleman et al, 2011), expression of these molecules in tumor cells and tumor-associated stroma, respectively, biopsy was performed after 10 years of follow-up on patients after biopsy, and correlations between IL-1 β/IL-1R1 expression and distant recurrence or bone recurrence were evaluated using a multivariate Cox model, IL-1 β in tumor cells with distant recurrence at any site (p ═ 0.0016), recurrence in bone only (p ═ 0.017) or recurrence in bone at any time (p ═ 0.017) were correlated with strong tumor cells (fig. 15) and with tumor stroma recurrence in bone (p ═ 0.044) and with no tumor stroma recurrence in tumor cells, thus a new tumor origin of IL-1R 462 was suggested that it is more likely to promote the recurrence in tumor cells than the tumor cells with the tumor stroma, and the tumor cells could be a new tumor recurrence in future, no recurrence of IL-1-free from tumor origin, IL-1- β.
Example 4
The Kanagilunumab PK profile and the hscRP profile for lung cancer patients were simulated.
Based on data from the CANTOS study, a model was generated to characterize the relationship between canarginous resistance Pharmacokinetics (PK) and hsCRP.
The following methods were used for this study: model construction was performed using first order condition estimation and interaction methods. The model describes the logarithm of time-resolved hsCRP as:
y(tij)＝y0,i+yeff(tij)
wherein y is0,iIs a steady state value and yeff(tij) Indicating a therapeutic effect and depending on systemic exposure. The treatment effect was described using an Emax-type model,
wherein E ismax,iIs the maximum possible response at high exposure, IC50iIs the concentration at which half of the maximal response is obtained.
Respective parameters Emax,iAnd y0,iAnd IC50iIs estimated as the sum of typical values, covpar coviAnd normal distribution between subject variability. The term covpar refers to the estimated covariate effect parameter, and coviIs the value of the subject covariate i. The covariates to be included are selected based on a check of the eta graph versus the covariates. The residual error is described as a combination of a proportional term and an additive term.
Log of baseline hscRP as all three parameters (E)max,i、y0,iAnd IC50i) The covariates of (a) are included. There are no other covariates in the model. The estimation accuracy of all parameters is high. The effect of the log of baseline hsCRP on the steady state value was less than 1 (equal to 0.67). This indicates that baseline hsCRP does not scale well to steady state values and that steady state values expose a regression relative to the baseline mean. The effect of the log of baseline hsCRP on IC50 and Emax was negative. Thus, patients with high hsCRP at baseline are expected to have a low IC50 and a large maximum decrease. Typically, the model diagnostic program confirms that the model well describes the available hsCRP data.
This model was then used to model the expected hsCRP response to select different dosing regimens in a population of lung cancer patients. Bootstrap methods (bootstrapping) were applied to construct populations with prospective inclusion/exclusion criteria representing potential lung cancer patient populations. Three different lung cancer patient populations, described only by the baseline hsCRP profile, were studied: all CANTOS patients (scenario 1), confirmed lung cancer patients (scenario 2) and advanced lung cancer patients (scenario 3).
The population parameters of the model and the variability between patients were assumed to be the same in all three scenarios. The PK/PD relationship for hscRP observed throughout the cants population was assumed to represent lung cancer patients.
The estimated number is the likelihood that hsCRP will be below the critical point, which may be 2mg/L or 1.8mg/L, by the end of
For the CANTOS PK data, a single chamber model with first order absorption and elimination was established. The model is expressed as an ordinary differential equation, and RxODE is used to model the time course of canargiunumab concentration given the individual PK parameters. The subcutaneous canaryitumumab dose regimen of interest was 300mg Q12W, 200mg Q3W, and 300mg Q4W. Exposure metrics (including Cmin, Cmax, AUC over different selected time periods and mean concentration at steady state Cave) were derived from simulated concentration-time curves.
The simulation in scenario 1 is based on the following information:
canatkinumab-alone exposure using RxODE simulation
PD parameter (which is y)0,i、Emax,iAnd IC50iThe components of (a): typical values (THETA (3), THETA (5), THETA (6)), covpar (THETA (4), THETA (7), THETA (8)), and covpar inter-subject variability (ETA (1), ETA (2), ETA (3))
Baseline hsCRP from all 10,059 patients from the CANTOS study (baseline hsCRP: mean 6.18mg/L, mean Standard Error (SEM) ═ 0.10mg/L)
First generating a prediction interval for the target estimator by randomly sampling 1000 THETA (3) - (8) from a normal distribution (where the fixed mean and standard deviation are estimated from the population PK/PD model); bootstrap 2000PK exposures, PD parameters ETA (1) - (3) and baseline hsCRP for all cants patients were then performed for each THETA (3) - (8) group. The 2.5%, 50%, and 97.5% percentiles of the 1000 estimates are reported as the point estimates and the 95% prediction interval.
The simulation in
single Kanaginumunumab PK exposure using RxODE simulation
PD parameters THETA (3) - (8) and ETA (1) - (3)
Baseline hsCRP for 116 CANTOS patients with confirmed lung cancer (baseline hsCRP: mean 9.75mg/L, SEM 1.14mg/L)
First generating a prediction interval for the target estimator by randomly sampling 1000 THETA (3) - (8) from a normal distribution (where the fixed mean and standard deviation are estimated from the population PKPD model); then for each THETA (3) - (8) group, 2000PK exposures, PD parameters ETA (1) - (3) were bootstrapped from all CANTOS patients, and 2000 baseline hsCRP was bootstrapped from 116 CANTOS patients with confirmed lung cancer. The 2.5%, 50%, and 97.5% percentiles of the 1000 estimates are reported as the point estimates and the 95% prediction interval.
In
Consistent with the model, the simulated canarginoumab PK was linear. The median and 95% prediction intervals of the concentration time spectra plotted on a natural log scale for 6 months are shown in figure 16 a.
The median of 1000 estimates of the proportion of subjects with hsCRP response at
Example 5A
PDR001 plus canarginoumab treatment increased effector neutrophils in colorectal tumors.
RNA sequencing was used to drill down the mechanism of action of Kanagilunumab (ACZ885) in cancer. CPDR001X2102 and CPDR001X2103 clinical trials evaluated the safety, tolerability, and pharmacodynamics of gabapentin (PDR001) in combination with other therapies. For each patient, tumor biopsies were taken both before treatment and at
FIG. 17 shows 21 genes that are increased on average in colorectal tumors treated with PDR001+ Canatkinumab (ACZ885) but not in colorectal tumors treated with PDR001+ everolimus (RAD 001.) treatment with PDR001+ Canatkinumab increased RNA levels of IL1B and its receptor IL1R2 the observations indicate that the on-target compensatory feedback of tumors increases IL1B RNA levels in response to IL-1 β protein blockade.
Notably, neutrophil-specific genes were increased in the case of PDR001+ canarginoumab, including FCGR3B, CXCR2, FFAR2, OSM, and G0S2 (shown in boxes in fig. 17). The FCGR3B gene is a neutrophil-specific isoform of the CD16 protein. The protein encoded by FCGR3B plays a key role in the secretion of reactive oxygen species in response to immune complexes, consistent with the function of effector neutrophils (Fossati G2002 Arthritis Rheum [ Arthritis & rheumatism ]46: 1351). Chemokines that bind CXCR2 translocate neutrophils from the bone marrow and into surrounding sites. In addition, an increase in CCL3 RNA was observed when treated with PDR001+ canarginoumab. CCL3 is a chemoattractant for neutrophils (Reichel CA 2012Blood 120: 880).
In summary, this compositional contribution analysis using RNA-seq data indicates that PDR001+ canajirimumab treatment increases effector neutrophils in colorectal tumors, whereas this increase is not observed with PDR001+ everolimus treatment.
Example 5B
Efficacy of canajirimonamab (ACZ885) in combination with sbatuzumab (PDR001) for the treatment of cancer.
Patient 5002 + 004 was a 56 year old male initially with stage IIC, microsatellite stable, moderately differentiated ascending colon adenocarcinoma (MSS-CRC) diagnosed in june 2012 and treated with a prior regimen.
Prior treatment regimens included:
1. folinic acid/5-fluorouracil/oxaliplatin, in the adjuvant case
2. Capecitabine chemical radiotherapy (metastatic condition)
3.5-Fluorouracil/Bevacizumab/folinic acid/irinotecan
4. Trifluridine and tipiracetam
5. Irinotecan
6. Oxaliplatin/5-fluorouracil
7.5-Fluorouracil/Bevacizumab/Tetrahydrofolic acid
8.5-Fluorouracil
At the beginning of the study, patients had extensive metastatic disease, including multiple liver and bilateral lung metastases, as well as paraesophageal lymph node, retroperitoneal and peritoneal disease.
The patient was treated with PDR 001400 mg (Q4W) every four weeks plus 100mg (Q8W) ACZ885 every eight weeks. The patient had stable disease after 6 months of treatment, then had significantly reduced disease, and confirmed a partial response of RECIST to treatment at 10 months. The patient subsequently developed progressive disease and the dose was increased to 300mg and then to 600 mg.
Example 6
Calculation of the gavojizumab dose for the cancer patient was selected.
Based on the available PK data for clinically effective doses to qualify worguzumab as revealed by the cants assay, the dose of gavaguzumab to treat cancers with at least a partial inflammatory basis was selected, considering that gavaguzumab (
Next, hsCRP exposure-response relationships were explored using pharmacological models, and clinical data were extrapolated to higher ranges. Since clinical data show a linear correlation between hsCRP concentration and kvojizumab concentration (all in log space), a linear model was used. The results are shown in FIG. 18 b. Based on this simulation, a gavaglus concentration between 10000ng/mL and 25000ng/mL was optimal, as hsCRP was greatly reduced in this range, with only a reduced benefit when gavaglus concentration was higher than 15000 ng/mL. However, since hsCRP has been significantly reduced in this range, a gavaglizumab concentration between 4000ng/mL to 10000ng/mL is expected to be effective.
Clinical data indicate that, following subcutaneous administration, the pharmacokinetics of gemtuzumab ozogamicin followed a linear two-compartment model with first-order absorption. The bioavailability of gemfibrozumab was about 56% when administered subcutaneously. Multiple dose kvojizumab (SC) simulations were performed for 100mg every four weeks (see fig. 18c) and 200mg every four weeks (see fig. 18 d). Simulations indicate that a trough concentration of approximately 10700ng/mL was administered every four weeks with 100mg of Gevojizumab. The half-life of gemtuzumab ozogamicin is about 35 days. The trough concentration of 200mg of gemfibrozumab administered every four weeks was approximately 21500 ng/mL.
Example 7
Preclinical data on the efficacy of anti-IL-1 β treatment.
Kanagilunumab is a human IgG1 antibody directed against IL-1 β and cannot be evaluated directly in a cancer mouse model because it does not cross-react with mouse IL-1 β A mouse surrogate anti-IL-1 β antibody has been developed and used to evaluate the effect of blocking IL-1 β in a cancer mouse model the isotype of the surrogate antibody is IgG2a, closely related to human IgG 1.
In the MC38 mouse model of colon cancer, modulation of Tumor Infiltrating Lymphocytes (TILs) was seen after a dose of anti-IL-1 β antibody (FIGS. 19 a-19C). the MC38 tumor was implanted subcutaneously in the flank of C57BL/6 mice, when tumors were between 100-150mm3, the mice were treated with a dose of isotype or anti-IL-1 β antibody. then the tumors were harvested and treated five days after this dose to obtain a single cell suspension of immune cells, cells were then stained ex vivo and analyzed by flow cytometry. after a single dose of IL-1 β blocking antibody, the tumor infiltrating CD4+ T cells increased while CD8+ T cells also increased slightly (FIG. 19 a). the increase in CD8+ T cells was minimal, but a more active immune response in the tumor microenvironment combined treatment might be possible to enhance this immune response.CD 4+ T cells could be further subdivided into
In the LL2 mouse model of lung cancer, a similar trend for a reduction in microenvironment immunosuppression was seen after a dose of anti-IL-1 β antibody (FIGS. 19d-19 f). LL2 tumors were implanted subcutaneously in the flank of C57BL/6 mice, and when tumors were between 100-fold 150mm3, the mice were treated with a dose of either isotype antibody or anti-IL-1 β antibody, then tumors were harvested and treated five days after this dose to obtain a single cell suspension of immune cells, then the cells were stained ex vivo and analyzed by flow cytometry, as assessed by expression of FoxP3 and Helios, the reduction in the Treg population (FIG. 19 d). FoxP3 and Helios were both used as markers of regulatory T cells, while they defined different subsets of Treg (Thornton et al, 2016) similar to the MC38 model, the reduction in the neutrophil and M2 (TAM2) populations after IL-1 blocking (T-1), and the reduction in the number of macrophages after active blocking of macrophages (TAM2) were found to be a reduction in the MCT 38 model of multiple myelosuppression of the tumor cells (MDN-19, SER-19, MDN-19, SERS-NSE, and NSE model.
TIL in the 4T1 triple negative breast cancer model also showed a trend towards a reduced microenvironment immunosuppression after one dose of mouse substituted for anti-IL-1 β antibody (fig. 19g-19 j.) when 4T1 tumor was implanted subcutaneously in the flank of Balb/c mice, mice were treated with either isotype or anti-IL-1 β antibody when the tumor was between 100-prime 150mm3, then tumors were harvested and treated five days after this dose to obtain a single cell suspension of immune cells, cells were then stained ex vivo and analyzed by flow cytometry after a single dose of anti-IL-1 β antibody, CD4+ T cells were reduced (fig. 19g), whereas in the CD4+ T cell population FoxP3+ Treg was reduced (fig. 19 h.) furthermore, after treatment of tumor-bearing mice, both TAM2 and neutrophil numbers were reduced (fig. 19 i.) all these data again demonstrate that IL-1 in the 4T1 mouse model of breast cancer also blocked the tumor-1 mouse model, the immune suppressive antibody was found to be reduced in combination with the immune suppression of this tumor-1 mouse model (fig. 19j), in addition to the immune suppression of tumor-mediated by
Even though these models are not completely associated with the same type of human cancer, the MC38 model is especially a good surrogate model for hypermutation/MSI (microsatellite instability) colorectal cancer (CRC). according to the transcriptomic characteristics of the MC38 cell line, the four driver mutations in this cell line correspond to known hot spots in human CRC, although they are located at different positions (efremeva et al, 2018.) although this does not make the MC38 mouse model the same as human CRC, this does mean that MC38 may be a relevant model for human MSICRC.
Even though these models are not completely associated with the same type of human cancer, the MC38 model is particularly a good surrogate model for hypermutated/MSI (microsatellite instability) colorectal cancer (CRC). According to the transcriptomic characteristics of the MC38 cell line, the four driver mutations in this cell line correspond to known hot spots in human CRC, although they are located at different positions (eframeova et al, 2018). Although this does not make the MC38 mouse model identical to human CRC, it does mean that MC38 may be a relevant model for human MSICC (Efremova M, et al Nature Communications 2018; 9:32)
Example 8
A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of canaryitumumab in combination with docetaxel compared to placebo in non-small cell lung cancer (NSCLC) patients previously treated with PD-L1 inhibitor and platinum-based chemotherapy
This is a 2-part study:
part 1: safe running-in
Prior to the randomization portion of the study, a safety break-in was performed to confirm the
At least 6 subjects were treated with full dose docetaxel and canargizumab dose level 1(DL 1): canaganuomab 200mg subcutaneous administration (s.c.) + docetaxel 75mg/m was administered intravenously (i.v.) on day 1 of each 21-day cycle2。
Subjects were evaluated for at least 2 complete treatment cycles (21 days per cycle; 42 days total) for safety assessment (DLT-dose limiting toxicity) to define RP 3R. Once the dose and schedule are determined, the randomized part of the study will be started.
Other patients may be included in the dose level 1(DL1) cohort if deemed necessary, or a decline to dose level-1 (DL-1) where the administration interval of canaryitumumab from Q3W to Q6W is increased while maintaining the dose of canaryitumumab and maintaining the dose and schedule of docetaxel may also be considered.
Section 2: double-blind, randomized, placebo-controlled fraction
After the safety break-in phase has been established at RP3R, the main test is started. After the subjects met all entry criteria, subjects were randomized into one of the following 2 treatment teams/group (docetaxel to canagerumumab or docetaxel to placebo) at a 1:1 ratio:
group A:
canagagenumumab (s.c as RP3R) + docetaxel 75mg/m2And i.v. Day-1 of every 21-day cycle (Q3W)
Group B:
placebo (s.c as RP3R) + docetaxel 75mg/m2i.v。Q3W
A treatment stage:
study treatment began on day 1 of cycle 1, with study treatment first administered. Subjects continued treatment until the investigator assessed recorded RECIST 1.1 disease progression, unacceptable toxicity (no further treatment), initiation of new anti-tumor therapy, withdrawal of consent, physician's decision, pregnancy, missed visits, death or sponsor termination of the study.
Each treatment cycle was 21 days (the cycle length of 21 days was fixed whether the dose of docetaxel and/or canaryitumumab was discontinued).
Inclusion criteria
1. Histologically confirmed locally advanced/metastatic (stage IIIB or IV according to AJCC/IASLC v.8) NSCLC
2. The subject has received a prior platinum-based chemotherapy for locally advanced or metastatic disease and a prior PD-L1 inhibitor therapy:
the subject may have received a platinum-based chemotherapy and a PD-L1 inhibitor for advanced or metastatic disease together (in the same treatment regimen) or sequentially (in two different treatment regimens) and progressed
Subjects receiving PD-L1 inhibitor as maintenance therapy (no progression of platinum-Duplex chemotherapy) and eligible for PD-L1 progression
Subjects receiving adjuvant or neo-adjuvant platinum duplex chemotherapy (after surgery and/or radiotherapy) and PD-L1 inhibitor and presenting with recurrent or metastatic disease within 12 months or 12 months of completion of treatment
Eligible subjects who relapse disease >12 months after platinum-based adjuvant or neoadjuvant chemotherapy, who also progressed during or after the platinum-duplex regimen and PD-L1 inhibitor (administered together or sequentially to treat the relapse)
Exclusion criteria
Subjects who met any of the following criteria did not qualify for inclusion in the study.
1. Patients who had previously received docetaxel, canargiunumab (or another IL-1 β inhibitor), or any other systemic therapy (rather than a platinum-based chemotherapy and a prior PD-L1 inhibitor) for locally advanced or metastatic NSCLC.
Note that: prior neoadjuvant or adjuvant therapy is not considered a systemic therapy for advanced NSCLC unless a relapse occurs within 12 months or 12 months of completion
2. Subjects found to have EGFR sensitizing mutations and/or ALK rearrangements by local laboratory testing
Note that: patients known to be positive for BRAF V600 mutation or ROS1 will be excluded
Note that: NSCLC patients with pure squamous cell tissue can begin treatment without EGFR or ALK detection or outcome.
Analysis of the Primary endpoint or endpoints
Safety break-in section
The primary endpoint was the incidence of dose-limiting toxicity associated with administration of canaryitumumab in combination with docetaxel within the first 42 days of dosing, and therefore the
Randomizing phase III part
The primary objective was to compare the Overall Survival (OS) of the docetaxel plus cana-genuinumab group compared to the docetaxel plus placebo group. OS is defined as the time from the date of randomization/start of treatment to the date of death for any reason.
The median Overall Survival (OS) for the docetaxel plus placebo group was expected to be around 8 months according to current data (Herbst et al 2016, Rittmeyer et al 2017). Treatment with docetaxel plus canargiunumab is expected to result in a 43% reduction in OS risk, i.e. an expected risk ratio of 0.57 (corresponding to an increase in median OS to 14 months under the exponential model assumption).
Example 9
The study population included four cohorts of patients:
queue 1, one-line mCRC: the patient had no prior intended systemic treatment for metastasis, nor had prior adjuvant therapy (except for radiosensitizers).
Safe break-in phase
The test included a safety break-in performed before the start of the
A safe dose of gemfibrozumab will be determined to be the
The combination partners are administered as follows:
cohort 1, gemfibrolizumab + FOLFOX + bevacizumab: bevacizumab was administered at 5mg/kgIV on
Extension phase
The goal of the extension phase was to evaluate the primary efficacy and safety of the combination therapy in each cohort. The main goal is the Progression Free Survival (PFS) rate evaluated in the specified months according to RECIST v 1.1. PFS is defined as the time from the date of the first dose of study treatment to the date of the first recorded radiological progression or any cause of death. Queue 1 will be evaluated at 16 months,
The extension phase will achieve at least 40 (20 high CRP and 20 low CRP) patients in cohort 1 and cohort 2 (each) and at least 20 (high CRP) patients in
The dosage will be based on a safe break-in result. In the extension phase, patients in cohort 1 and
Patients will continue to receive study treatment and follow-up on the assessment schedule until disease progression as specified by RECIST 1.1 is reached or until the study is discontinued for any reason.
EXAMPLE 10 randomized, double-blind phase III study of Lanolizumab + platinum-based chemotherapy with or without Carnagilunumab as first line therapy for locally advanced or metastatic non-squamous and squamous non-small cell lung cancer subjects
The study population included adult patients with first-line locally advanced stage IIIB (not eligible for definitive chemo-radiotherapy) or stage IV metastatic non-small cell lung cancer (NSCLC) and no EGFR mutation or ALK translocation. Only patients who have not been previously treated with any systemic anti-cancer therapy are included, with the exception of neoadjuvant or adjuvant therapy (if relapses occur more than 12 months from the end of the therapy). Furthermore, the subject should be free of known B-RAF mutations or ROS-1 genetic abnormalities.
Safe break-in before beginning phase III study
The nonrandomized safety run-in portion of this study will be completed with canajinoumab in combination with lanolizumab and three platinum-based duplex chemotherapies: carboplatin + pemetrexed (non-squamous tumor patients), cisplatin + pemetrexed (non-squamous tumor patients) and carboplatin + paclitaxel (squamous or non-squamous tumor patients). Non-squamous oncology histology subjects receiving paclitaxel-carboplatin and lanolizumab in a safe break-in and achieving Stable Disease (SD) or better will receive pemetrexed maintenance therapy after completion of induction. The dose of canarginoumab will be started at 200mg (Q3W) every three weeks.
The primary objective was to determine the recommended phase III dose regimen of canargizumab in combination with lanolizumab and chemotherapy (RP 3R). Secondary objectives were to characterize safety and tolerability, pharmacokinetics, immunogenicity, and to evaluate preliminary clinical antitumor activity.
When dose-limiting toxicity (DLT) of at least 6 evaluable patients in the 3 treatment cohorts from the initial dose level to the start observed lasted at least 42 days, an analysis will be performed to determine the recommended phase III dose regimen (RP3R), establishing RP 3R. Evaluable patients are defined as follows:
has received at least 2 cycles (21 days ═ 1 cycle) of a full dose of lanolizumab 200mg IV and at least 75% of the planned dose of 2 cycles of chemotherapy, and
200mg s.c canarginoumab every 3 weeks or every 6 weeks that has received at least 2 doses, and
for adverse events, at least 42 days had been followed.
Where dose decrementing is required, additional patients may be enrolled at other dose levels (e.g., dose level minus 1, maintaining doses of other components, but extending the interval between administrations of canargizumab to 6 weeks). The RP3R to be administered in combination with the canargizumab based platinum will be determined according to the safety break-in of the study.
Randomized phase III part of the study
Approximately 600 patients will be randomized to receive canargizumab or a matched placebo combination inducing platinum-based chemotherapy (platinum + pemetrexed for non-squamous histology, platinum + taxane-based chemotherapy for squamous histology) + lanolizumab, administered for up to 4 cycles, followed by canargizumab or a matched placebo combination lanolizumab maintenance therapy (non-squamous histology patients will also receive chemotherapy during maintenance therapy).
The main objective was to compare Progression Free Survival (PFS) derived from RECIST 1.1 with Overall Survival (OS) of the two treatment groups (canajirimumab versus placebo). Secondary objectives are to assess Overall Response Rate (ORR), Disease Control Rate (DCR), response time, duration of response, safety profile, pharmacokinetic immunogenicity, patient reported outcomes.
PFS is defined as the time from the date of randomization to the date of the first recorded disease progression or death of any cause evaluated according to RECIST 1.1 local investigators. The OS is defined as the time from the randomized date to death of any cause. PFS2 was defined as the time from the date of randomization to the first recorded progression in the next line of treatment or death (whichever occurred first). ORR is defined as the proportion of subjects with the best overall response or partial response.
Treatment will continue until disease progression is recorded or treatment is discontinued for any reason. However, for patients who are clinically stable and gaining clinical benefit, who have PD and tolerate treatment by immune response criteria (icapd of iRECIST), treatment beyond disease progression can continue as per RECIST 1.1.
Table 1. baseline clinical characteristics of participants in CANTOS among participants with and without sporadic cancer during follow-up.
Means values within the set of characteristic levels of the continuous variables, and percentages of the binary variables
Table 2 incidence (every 100 years) and risk ratio for all sporadic, lung and non-lung cancers in CANTOS.
Table 3. effect of canarginoumab on platelets, leukocytes, neutrophils, and erythrocytes after 12 months of reported adverse events and treatment with study drug during cants compared to placebo.
+ standardized MedDRA queries
Value per cubic millimeter
**x 1012
Table 4 study groups are stratified for incidence (per 100 years), number of severe adverse events (N), and safety laboratory data (%, N) selected for treatment.
+ standardized MedDRA queries
Category of + sponsor adverse events of particular interest
Table 5. ratio of hsCRP < critical point at month 3 (median and 95% prediction interval).
# # increases in severity for lung cancer from scenario 1 to
Table s1. baseline clinical characteristics of CANTOS participants, depending on treatment status.
STEMI ═ ST elevation myocardial infarction; PCI is percutaneous coronary intervention; CABG ═ coronary artery bypass surgery; hsCRP ═ high density C-reactive protein; HDL ═ high density lipoprotein cholesterol; LDL ═ low density lipoprotein cholesterol; eGFR ═ estimation of glomerular filtration rate
β blockers, nitrates or calcium channel blockers
The median values of all measured plasma variables and body mass indices are given
Table s2 incidence (every 100 years) and hazard ratio of lung cancer in current and past smokers.
Table s3. incidence per 100 human years, and incidence (number) of non-lung cancer in CANTOS of lung cancer type and other specific sites.
NA-if the number of events is <10, no significance test is performed.
Table s4. susceptibility analysis was performed on incidence (every 100 people years) and risk ratio based on all reported cancers in CANTOS rather than judged cancers.
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