Compositions and methods for treating cancer
阅读说明：本技术 治疗癌症的组合物和方法 (Compositions and methods for treating cancer ) 是由 赵启洪 J·法诺利 M·古鲁拉真 S·魏 于 2019-01-22 设计创作，主要内容包括：本发明涉及用包含CCR2/5双重拮抗剂,例如N-((1R,2S,5R)-5-(叔丁基氨基)-2-((S)-3-(7-叔丁基吡唑并[1,5-a][1,3,5]三嗪-4-基氨基)-2-氧基吡咯烷-1-基)环己基)乙酰胺；单克隆抗体,例如纳武单抗；和/或化学疗法的组合治疗受试者的癌症的方法。(The present invention relates to the use of dual antagonists comprising CCR2/5, such as N- ((1R,2S,5R) -5- (tert-butylamino) -2- ((S) -3- (7-tert-butylpyrazolo [1,5-a ] [1,3,5] triazin-4-ylamino) -2-oxopyrrolidin-1-yl) cyclohexyl) acetamide; monoclonal antibodies, such as nivolumab; and/or chemotherapy in a subject.)
1. A method of treating cancer in a subject, comprising administering to the subject a combination of: a monoclonal antibody, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a combination thereof,
and/or chemotherapy.
2. A method of treating cancer in a subject, comprising administering to the subject a combination of: a monoclonal antibody and a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a combination thereof,
3. the method of claim 1, wherein the amount of the compound of formula (I) administered to the subject is from about 25 mg/day to about 1200 mg/day.
4. The method of claim 3, wherein the amount of the compound of formula (I) administered to the subject is from about 100 mg/day to about 1200 mg/day.
5. The method of claim 4, wherein the amount of the compound of formula (I) administered to the subject is from about 200 mg/day to about 1200 mg/day.
6. The method of claim 5, wherein the amount of the compound of formula (I) administered to the subject is from about 300 mg/day to about 1200 mg/day.
7. The method of claim 6, wherein the amount of the compound of formula (I) administered to the subject is from about 600 mg/day to about 1200 mg/day.
8. The method of claim 3, wherein the amount of the compound of formula (I) administered to the subject is from about 25 mg/day to about 600 mg/day.
9. The method of claim 8, wherein the amount of the compound of formula (I) administered to the subject is from about 25 mg/day to about 600 mg/day.
10. The method of claim 9, wherein the amount of the compound of formula (I) administered to the subject is from about 100 mg/day to about 600 mg/day.
11. The method of claim 10, wherein the amount of the compound of formula (I) administered to the subject is from about 200 mg/day to about 600 mg/day.
12. The method of claim 11, wherein the amount of the compound of formula (I) administered to the subject is from about 300 mg/day to about 600 mg/day.
13. The method of claim 1, wherein the compound of formula (I) is administered in doses of 300mg and 600mg, once or twice daily.
14. The method of claim 1, wherein the cancer is a malignant solid tumor.
15. The method of claim 14, wherein the cancer is metastatic and/or unresectable.
16. The method of claim 15, wherein the cancer is selected from colorectal cancer, pancreatic cancer, liver cancer, and lung cancer, or a combination thereof.
17. The method of claim 16, wherein the cancer is colorectal cancer or pancreatic cancer.
18. The method of claim 17, wherein the subject receives at least one prior therapy for treating the cancer.
19. The method of claim 17, wherein the subject is untreated.
20. The method of claim 19, wherein the monoclonal antibody is nivolumab.
21. The method of claim 20, wherein said nivolumab is administered by intravenous infusion at a dose of about 480mg every 4 weeks.
22. The method of claim 21, wherein the chemotherapy is FOLFIRI or Gem/ABRAXANE.
Technical Field
The present invention relates to methods of treating cancer in a subject with a combination of a dual CCR2/5 antagonist, monoclonal antibody and/or chemotherapy. In some embodiments, the tumor is a solid tumor. In certain embodiments, the solid tumor is pancreatic cancer, colorectal cancer, or a combination thereof.
Background
Pancreatic adenocarcinoma is the third leading cause of cancer death in the united states and is expected to be the second leading cause of cancer death by the year 2020. The 5-year survival of pancreatic cancer is frustrating, with only 8% surviving 5 years from diagnosis. Patients with metastatic disease have frustrating outcomes with a median survival of less than 1 year. Patients with metastatic pancreatic cancer have limited treatment options. Gemcitabine in combination with nab-paclitaxel was approved for 1L treatment in patients with advanced pancreatic cancer. Patients with advanced pancreatic cancer can be treated with 5-fluorouracil (5-FU)/liposomal irinotecan in a two-line (2L) setting. However, these drugs are generally poor in efficacy, with low overall response rates, with a median PFS of only 2 to 3 months, and a median Overall Survival (OS) of 6 to 7 months. Although chemotherapy can improve survival, there are still significant toxic effects and all patients eventually die from the disease. The development of new therapies for pancreatic cancer is an unmet area.
Worldwide, colon cancer (including rectal cancer) is the third most common cancer in men and the second most common cancer in women. In 2013, in the United States (US), an estimated 142,820 new cases of colon or rectal cancer (CRC) were diagnosed, with an estimated 50,830 cases dying from CRC. At the time of initial diagnosis, approximately 25% of patients suffer from metastatic disease and nearly 50% of patients develop metastases, which results in a high mortality rate in patients reporting CRC. The treatment options for patients with metastatic colon or rectal cancer (mCRC) are mainly regimens comprising 5-fluorouracil (5-FU) in combination with oxaliplatin or irinotecan (FOLFOX or FOLFIRI) in combination with a biologic agent such as bevacizumab. The EGFR inhibitors cetuximab and panitumumab may also be selected if the KRAS status is not mutated. In later therapy, regorafenib showed an improvement of about 6 months in overall survival of patients previously treated with chemotherapy. Indicating that the survival results for trifluorothymidine/tipiracil were similar. Despite the many initial treatment options for mCRC, the benefits of these therapies are limited and complete radiographic responses rarely occur, highlighting the need for more effective therapies.
Checkpoint inhibitors have changed cancer care, but extending these benefits to more patients may require other approaches. Cysteine-cysteine (C-C) chemokine receptor 2(CCR2) and C-C chemokine receptor 5(CCR5) are 2 chemokine receptors that are expressed on myeloid cells and T cell infiltrates in the Tumor Microenvironment (TME) and appear to be the key drivers of migration and accumulation of myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived inhibitory cells, into the TME (Mantovani, a. et al, nat. rev. clin. oncol.,2017Jan 24.doi: 10.1038/nrcinc.2016.217; leskhin, a.m. et al, Cancer Res 72(4):876-86 (2012); schker, e 2012. et al, j.immunol.,189 immunol.,189(12):5602-11 (11)). In addition, both receptors have shown important roles in the trafficking of regulatory T cells (tregs) to TMEs (Loyher, p.l. et al, Cancer res.,76(22):6483-94 (2016); Tan m.c. et al, j.immunol.,182(3):1746-55 (2009)). In addition to playing a major role in driving immune cells toward TME, it has recently been shown that inhibition of CCR5 repolarizes TAM from the immunosuppressive M2 phenotype to the immunologically activated M1 phenotype (Halama, N. et al, Cancer Cell,29(4): 587-. Each receptor has individually proven to be an important participant in a number of cancer models including pancreatic cancer (Sanford, d.e. et al, clin. cancer res.,19(13):3404-15 (2013); Tan m.c. et al, j.immunol.,182(3):1746-55(2009)), colon cancer (Afik, r. et al, j.exp.med.,213(11):2315-31 (2016); Tanabe, y. et al, 7(30):48335-45(2016)), liver cancer (Li, x. et al, Gut,66(1):157-67 (2017); ashi, n 2012 et al, Hepatology,58 (2016) (1021-30) (3); and, (3) and lung cancer (ama, a. et al, am. 191.g., 191.7); c. 23, 14, 8, 14, c.) (26, 14, 7, 3) (2016). CCR 2-selective antagonists and CCR 5-selective antagonists in combination with chemotherapy show direct evidence of a mechanism and clinical response to pancreatic and colorectal cancer, respectively, in patients (Nywening, T.M. et al, Lancet Oncol.,17(5):651-62 (2016); Halama, N. et al, cancer cell 29(4): 587-.
The use of dual CCR2/5 antagonists in combination with anti-PD-1 antibodies and/or chemotherapy has not been reported, and represents a new approach with the potential to extend the immunooncological benefits to patients for whom existing therapies are not sufficiently effective. In addition, targeted therapy of multiple non-redundant molecular pathways that modulate immune responses can enhance anti-tumor immunotherapy. There remains a need for combination therapies with acceptable safety and high efficacy that enhance anti-tumor immune responses compared to monotherapy and other immunotherapy combinations.
Disclosure of Invention
The present invention relates to a method of treating cancer in a subject comprising administering to the subject a combination of: CCR2/5 dual antagonists, monoclonal antibodies and/or chemotherapy, and the like.
In some embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is colorectal cancer, pancreatic cancer, liver cancer, and lung cancer, or a combination thereof. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is pancreatic cancer.
In some embodiments, the monoclonal antibody is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1. In some embodiments, the anti-PD-1 antibody binds to the same epitope as nivolumab. In certain embodiments, the anti-PD-1 antibody is nivolumab.
In some embodiments, the dual CCR2/5 antagonist is the equivalent dual antagonist of CCR2 and CCR 5. In certain embodiments, the dual CCR2/5 antagonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof or a combination thereof,
n- ((1R,2S,5R) -5- (tert-butylamino) -2- ((S) -3- (7-tert-butylpyrazolo [1,5-a ] [1,3,5] triazin-4-ylamino) -2-oxopyrrolidin-1-yl) cyclohexyl) acetamide.
In some embodiments, the chemotherapeutic agent is selected from nab-paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, and irinotecan.
Drawings
Figure 1 illustrates a synergistic combination of compound a and antibody B against progression of mouse colon tumor (MC 38).
Figure 2 illustrates a synergistic combination of compound a and antibody B against progression of mouse colon tumor (MC 38).
Figure 3 illustrates a synergistic combination of compound a and antibody B against progression of mouse colon tumor (CT 26).
Detailed Description
The present application may be understood more readily by reference to the following detailed description taken in conjunction with the accompanying drawings and the examples, which form a part of this application. It is to be understood that this invention is not limited to the particular devices, methods, applications, conditions or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention. Furthermore, as used in the specification, including the appended claims, the singular forms "a," "an," and "the" include the plural, and reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise.
The term "and/or" as used in this application should be taken as specifically disclosing each of the two specified features or components, with or without the other. Thus, the term "and/or" as used in phrases such as "a and/or B" in this application is intended to include "a and B", "a or B", "a" (alone) and "B" (alone). Likewise, the term "and/or" as used in phrases such as "A, B and/or C" is intended to encompass the following: A. b and C; A. b or C; a or C; a or B; b or C; a and C; a and B; b and C; a (alone); b (alone); and C (alone).
As used in the specification and claims, the term "comprising" may include embodiments "consisting of … …" and "consisting essentially of … …". As used herein, the terms "comprising," "including," "having," "may," "containing," and variations thereof, are intended to be open-ended transition phrases, terms, or words that specify the presence of the stated components/steps and allow for the presence of other components/steps. However, such description should be construed as also describing the compositions or methods as "consisting of and" consisting essentially of the recited compounds, which allows for the mere presence of the named compounds along with any pharmaceutical carriers and excludes other compounds.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. For example, the concise dictionary of biomedicine and molecular biology, Juo, Pei-Show, second edition, 2002, CRC Press; dictionary of cell and molecular biology, third edition, 1999, academic Press; and "dictionary of Oxford biochemistry and molecular biology", revised edition, 2000, Oxford university Press, which provide a general dictionary for many of the terms used in this application.
Units, prefixes, and symbols are expressed in their international system of units (SI) accepted form. Numerical ranges include the numbers defining the range. The headings provided herein are not limitations of the various aspects of the disclosure which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the entire specification.
All ranges disclosed herein are inclusive of the recited endpoints and independently combinable (e.g., a range of "200 mg to 600 mg" is inclusive of the endpoints 200mg and 600mg, and all intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; it is not precise enough to include values that approximate these ranges and/or values.
Approximating language, as used herein, may be applied to modify any quantitative representation that may vary without resulting in a change in the basic function to which it is related. Accordingly, the terms "about" and "substantially" modified values may not be limited to the precise values specified, in some instances. In at least some instances, the approximating language may correspond to the precision of an instrument for measuring the value. The modifier "about" should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "about 100 to about 200" also discloses the range "100 to 200". The term "about" can mean ± 10% of the indicated value. For example, "about 10%" may mean a range of 9% to 11%, and "about 1" may mean 0.9 to 1.1. Other meanings of "about" may be seen in the context, e.g. rounding off, so that e.g. "about 1" may also mean 0.5 to 1.4.
A dual CCR2/5 antagonist refers to a small molecule antagonist that binds effectively to the CCR2 and CCR5 receptors and produces effective dual inhibition of in vitro receptor-mediated functions, such as CCR 2-and CCR 5-mediated functions, such as calcium flux and chemotaxis in response to their respective cognate ligands. Compounds having dual CCR2/5 inhibitory activity are reported, for example, in U.S. patent No. 8,383,812 and U.S. patent No. 7,163,937.
U.S. patent No. 7,163,937, incorporated herein by reference, discloses CCR2/5 dual antagonists including (S) -1- ((1S,2R,4R) -4- (isopropyl (methyl) amino) -2-propylcyclohexyl) -3- ((6- (trifluoromethyl) quinazolin-4-yl) amino) pyrrolidin-2-one (hereinafter referred to as compound a). The structure of the compound A is
U.S. patent No. 8,383,812 (incorporated herein by reference) discloses CCR2/5 dual antagonists, which include compounds of formula (I):
n- ((1R,2S,5R) -5- (tert-butylamino) -2- ((S) -3- (7-tert-butylpyrazolo [1,5-a ] [1,3,5] triazin-4-ylamino) -2-oxopyrrolidin-1-yl) cyclohexyl) acetamide (hereinafter referred to as Compound C).
As shown, for example, compound a effectively blocked the binding of CCL2 (also known as MCP-1) (a ligand for CCR2) to cells expressing mouse CCR 2; effectively block mouse CCL4 (also known as MIP-1 β) (ligand for CCR5) from cells expressing mouse CCR 5; effectively inhibit mouse CCL2 and mouse CCL 4-induced functions (calcium flux, integrin CD11b upregulation); and is pharmacologically related to compound C (table 1).
TABLE 1 mouse CCR2/5 potency of Compound A and human potency of Compound C
Assays for inhibiting ligand binding to CCR 2-expressing cells and CCR 5-expressing cells
Human CCR2 and CCR5 binding assays were established using human peripheral blood mononuclear cells (hPBMC) and human T cells, respectively, using 125I-human MCP-1 and 125I-human MIP-1 β as tracer ligands, hPBMC and human T cells were isolated from human leukapheresis samples using standard protocols, the isolated cells were washed (hPBMC for CCR2 binding and human T cells for CCR5 binding) and diluted to 1x107/ml in binding buffer (RPMI-1640, 0.1% BSA, 20mM Hepes, pH 7.4), 125I-MCP-1 and 125I-MIP-1 β (NEN/Perk Elmer) diluted to 0.45 nM. in binding buffer to 3 times the final concentration used for binding assays.binding assays were performed using 96-well filter plates (Millipore) and evaluated for MCP binding reactions (150. mu.78 each of MIP-1 and-1 β was included as follows5Individual cells, 0.15nM125I-MCP-1 or 125I-MIP-1 β, and Compound C, such that the final concentration ranges from 0nM to 100 nM., plates were incubated at room temperature for 30 minutes, then washed 3 times with RPMI-1640, 0.1% BSA,0.4M NaCl,20mM Hepes, pH 7.4 using vacuum manifold filtration (Millipore). after washing, plates were air dried at room temperature for 60 minutes, then 25.
Assays that inhibit binding of mouse ligands to mouse CCR2 and CCR5 were established in a manner similar to the human assay except that the WEHI-274.1 mouse monocyte cell line and L1.2 cells stably expressing mouse CCR5 were used as a source of cells expressing mouse CCR2 and mouse CCR5, respectively, and mouse MCP-1 and mouse MIP-1 β were used as tracer ligands for mouse CCR2 and CCR5, respectively.
Assays for inhibiting CCR2 and CCR5 mediated calcium flux in cells
Binding of MCP-1 to CCR2, or binding of MIP-1 β to CCR5, results in a cascade of G-protein coupled signal transduction pathways. One of these is the mobilization of calcium, which is important for the up-regulation and activation of downstream cellular functions, such as integrin (CD11 b). Intracellular calcium mobilization can be measured in a fluorescence imaging plate reader (FLIPR) because of the increase in fluorescence emitted by a calcium-binding fluorophore (e.g., fluo-3) when cells preloaded with the fluorophore are stimulated by MCP-1.
Human CCR 2-mediated intracellular calcium flux measurements were established using the human monocyte cell line THP-1. THP-1 cells were first loaded with fluorophore by resuspending them in glucose and HEPES buffered PBS (pH 7.4) containing 4. mu.M fluo-3 (molecular probe) and 1.25mM probenecid, and then incubated for 60 min at 37 ℃. After washing once to remove excess fluo-3, cells were resuspended in wash buffer with 1.25mM probenecid (containing RPMI without phenol red) and at 2 × 105Perwell into 96-well plates. Compound C dilutions or separate buffers were added to each well at concentrations ranging from 0 to 100nM, centrifuged and incubated for 10 min. Place the plate at FLIPR-1TM(Molecular Devices) the device uses an argon ion laser to excite cells and automatically adds human MCP-1 while monitoring fluorescence changes.then adds recombinant human MCP-1(PeproTechInc.) to a final concentration of 10 nM. to monitor fluorescence shift and automatically calculates the shift between basal peaksHT1080/CCR5, in which endogenous CCR5 is upregulated by Random Activation of Gene Expression (RAGE) technology, was followed by a similar procedure as described above.
Assays for inhibition of mouse CCR2 and CCR5 mediated calcium flux in response to their respective ligands were established in a manner similar to the human assay, except that the WEHI-274.1 mouse monocyte cell line and L1.2 cells stably expressing mouse CCR5 were used as a source of cells expressing mouse CCR2 and CCR5, respectively, and mouse MCP-1 and mouse MIP-1 β were used as ligands for mouse CCR2 and CCR5, respectively.
Assay for inhibiting CCR2 and CCR5 mediated upregulation of CD11b integrin in whole blood
A CCR2 dependent CD11b upregulation assay was established with human whole blood. Whole blood (100. mu.l) was preincubated with compound at a concentration range of C for 10 minutes at 37 ℃. Human recombinant MCP-1 (10. mu.l, 100nM) was then added to each reaction to a final concentration of 10nM, except for the unstimulated control reaction. The reaction was incubated at 37 ℃ for 30 minutes. After incubation, 1ml ice cold FACS (PBS with 10% FBS) buffer was added and the samples were centrifuged at 1500rpm for 5 minutes and then resuspended in 50 μ l FACS buffer. Cells were then incubated with 20 μ l of anti-CD 14-FITC/anti-CD 11b-PE solution on ice for 20 minutes in the dark, and 1ml of 1 XFACS lysate (Becton Dickinson) was added to each reaction. The samples were then incubated on ice for 30 minutes in the dark. After fixation and erythrocyte lysis, cells were centrifuged and resuspended in 200 μ l FACS lysate. Using FACSCaliburTMThe samples were analyzed by flow cytometry within 1 hour after staining. Using CellQuestProTMData collection and analysis was performed by the software sequential gating strategy was used to analyze the CD14high CD11b + monocyte population for analysis, CD11b was measured as Median Fluorescence Intensity (MFI) for analysis similar procedures were used for mouse CCR5 except MIP-1 β (50nM) was used as the ligand.
A mouse CCR 2-dependent CD11b upregulation assay was established using C57BL/6 mouse whole blood. Whole blood (100ul) was preincubated with a range of concentrations of Compound C for 30 min at 37 ℃. Mouse recombinant MCP-1 was then added to each reaction to a final concentration of 10nM, except for the unstimulated control reaction.The reaction solution was incubated at 37 ℃ for 15 minutes. After incubation, 1ml ice cold FACS (PBS with 10% FBS) buffer was added and the samples were centrifuged at 1500rpm for 5 minutes and resuspended in 50 μ l FACS buffer. Cells were then incubated with 20 μ l of anti-F4/80-PE/anti-mouse CD11b-APC solution on ice for 20 minutes in the dark, and 1ml of 1 XFACS lysate (Becton Dickinson) was added to each reaction. The samples were then incubated on ice for 20 minutes in the dark. After fixation and erythrocyte lysis, cells were centrifuged and resuspended in 200 μ l FACS lysate. Using FACSCaliburTMSamples were analyzed within 1 hour after flow cytometry staining data collection and analysis was performed using Flowjo software sequential gating strategy for analysis of F4/80+ CD11b + monocyte populations for analysis CD11b was measured as Median Fluorescence Intensity (MFI) for analysis a similar procedure was used for mouse CCR5 as described for mouse CCR2 except that the ligand was mouse MIP-1 β (50 nM).
Since compound C has poor mouse PK and mouse CCR2 titers, compound a was used as a mouse surrogate for the CCR2/5 dual antagonist to be evaluated as monotherapy and in combination with anti-PD 1 antibody in a tumor mouse model.
Some embodiments relate to a method of treating cancer in a subject, comprising administering to the subject a combination of: monoclonal antibodies, CCR2/5 dual antagonists and/or chemotherapy.
Some embodiments relate to a method of treating cancer in a subject, comprising administering to the subject a combination of: monoclonal antibodies and dual CCR2/5 antagonists.
Some embodiments relate to a combination of monoclonal antibodies, CCR2/5 dual antagonists and/or chemotherapy for the treatment of cancer.
Some embodiments relate to a combination of a monoclonal antibody and a dual CCR2/5 antagonist for use in the treatment of cancer.
In some embodiments, the combination described herein may comprise the administration of more than one monoclonal antibody.
In some embodiments, the dual CCR2/5 antagonist is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a combination thereof, which is administered to a subject in a single daily dose, or the total daily dose may be administered in divided doses two, three or four times daily. In certain embodiments, the total daily dose is administered as a once daily dose or twice daily dose. The amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be from about 100 mg/day to about 1200 mg/day. For example, the amount of a compound of formula (I) administered to a subject can be about 10 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 200 mg/day, 300 mg/day, 400 mg/day, 500 mg/day, 600 mg/day, 700 mg/day, 800 mg/day, 900 mg/day, 1000 mg/day, 1100 mg/day, and 1200 mg/day. In certain embodiments, the amount of the compound of formula (I) administered to a subject may be from about 10 mg/day to about 1200 mg/day; about 25 mg/day to about 1200 mg/day; about 50 mg/day to about 1200 mg/day; about 100 mg/day to about 1200 mg/day; from about 200 mg/day to about 1200 mg/day; about 300 mg/day to about 1200 mg/day; about 300 mg/day to about 1200 mg/day; about 400 mg/day to about 1200 mg/day; from about 500 mg/day to about 1200 mg/day; from about 600 mg/day to about 1200 mg/day. In certain embodiments, the amount of the compound of formula (I) administered to a subject may be from about 10 mg/day to about 600 mg/day; about 25 mg/day to about 600 mg/day; about 50 mg/day to about 600 mg/day; about 100 mg/day to about 600 mg/day; about 200 mg/day to about 600 mg/day; from about 300 mg/day to about 600 mg/day. In certain embodiments, the amount of the compound of formula (I) administered to a subject may be from about 10 mg/day to about 300 mg/day; about 25 mg/day to about 300 mg/day; about 50 mg/day to about 300 mg/day; about 100 mg/day to about 300 mg/day; from about 200 mg/day to about 400 mg/day. In certain embodiments, the amount of the compound of formula (I) is administered in doses of 300mg and 600mg, once or twice daily.
The amount of the compound of formula (I) described herein is based on the free form, i.e., non-salt form, of the compound of formula (I). If a salt is administered, the amount needs to be calculated based on the molecular weight ratio between the salt and the free form.
"pharmaceutically acceptable" means approved or approvable by a regulatory agency of the federal or a state government or by a corresponding agency of a country outside the united states (or listed in the united states). The pharmacopeia or other generally recognized pharmacopeia may be used in animals, more particularly in humans.
By "pharmaceutically acceptable salt" is meant a salt of a compound of the present application which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. In particular, such salts include: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or a salt formed by coordinating with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). By way of example only, salts also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; when the compound contains a basic functional group, it is a salt of a non-toxic organic or inorganic acid, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like.
In general, these salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or in a mixture of water and an organic solvent. Generally, nonaqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. A list of suitable salts is available from Allen, Jr., L.V., ed., Remington: The Science and Practice of Pharmacy,22nd Edition, pharmaceutical Press, London, UK (2012).
By "pharmaceutically acceptable excipient" is meant a diluent, adjuvant, excipient, or carrier with which the compound of the present application is administered. "pharmaceutically acceptable excipient" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, e.g., an inert substance, that is added to a pharmacological composition or that otherwise serves as a vehicle, carrier, or diluent to facilitate administration of the agent and is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, stearates, silica, polyvinyl alcohol, lubricants, talc, titanium dioxide, iron oxide, and polyethylene glycol.
"subject" includes humans. The terms "human", "patient" and "subject" are used interchangeably herein.
In one embodiment, "treating" or "treatment" any disease or disorder refers to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one clinical symptom thereof). In another embodiment, "treating" or "treatment" refers to ameliorating at least one physical parameter that may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both physically and physiologically modulating a disease or disorder. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of a disease or disorder.
The term "antibody" and similar terms refer in a broad sense and include immunoglobulin molecules, including monoclonal antibodies (e.g., murine, human adapted, humanized and chimeric monoclonal antibodies), antibody fragments, bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, and single chain antibodies. Depending on the heavy chain constant domain amino acid sequence, immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG 4. Antibody light chains of any vertebrate species can be assigned to one of two distinctly different types, namely κ and λ, based on the amino acid sequences of their constant domains.
"monoclonal antibody" refers to a population of antibody molecules having a single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope or, in the case of bispecific monoclonal antibodies, have dual binding specificities for two different epitopes. Thus, a monoclonal antibody refers to a population of antibodies having a single amino acid composition in each heavy chain and each light chain, except for possible well-known changes, such as the removal of the C-terminal lysine from the antibody heavy chain. Monoclonal antibodies may have heteroglycosylation in the antibody population. Monoclonal antibodies may be monospecific or multispecific, or monovalent, bivalent, or multivalent. The term monoclonal antibody includes bispecific antibodies.
anti-PD-1 antibodies useful in the present invention
Any anti-PD-1 antibody known in the art can be used in the methods described herein. In particular, various human monoclonal antibodies that specifically bind to PD-1 with high affinity are disclosed in U.S. patent No. 8,008,449. Various anti-PD-1 humanized antibodies disclosed in U.S. patent No. 8,008,449 have been shown to exhibit one or more of the following characteristics: (a) with KDIs 1x10-7M or less binds to human PD-1 as determined by surface plasmon resonance using a Biacore biosensor system; (b) does not substantially bind human CD28, CTLA-4 or ICOS; (c) increasing T cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay; (d) increasing interferon- γ production in an MLR assay; (e) increasing IL-2 secretion in an MLR assay; (f) binds to human PD-1 and cynomolgus monkey PD-1; (g) inhibit the binding of PD-L1 and/or PD-L2 to PD-1; (h) stimulating an antigen-specific memory response; (i) stimulating an antibody response; and (j) inhibiting tumor cell growth in vivo. anti-PD-1 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some embodiments at least five of the aforementioned characteristics.
Other anti-PD-1 monoclonal antibodies have been described, for example, in U.S. patent nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509, U.S. publication No. 2016/0272708, and the following PCT publications: WO 2012/145493, WO2008/156712, WO 2015/112900, WO 2012/145493, WO 2015/112800, WO 2014/206107, WO2015/35606, WO 2015/085847, WO2014/179664, WO 2017/020291, WO 2017/020858, WO2016/197367, WO 2017/024515, WO 2017/025051, WO 2017/123557, WO 2016/106159, WO2014/194302, WO2017/040790, WO2017/133540, WO 2017/132827, WO2017/024465, WO2017/025016, WO 2017/106061.
In some embodiments, the anti-PD-1 antibody is selected from the group consisting of Nantuzumab (also known as "OPDIVO"; previously designated as 5C4, BMS-936558, MDX-1106, or ONO-4538), pembrolizumab (Merck, also known as "KEYTRUDA", Pabolizumab, and MK-3475. see WO 2008/156712), PDR001 (Novartis; see WO 2015/112900), MEDI-0680 (AstraZeneca; AMP-514; see WO 2012/145493), cimiral mab (REGN-2810) (Regeneron; see WO 2015/112800), JS001(TAIZHOU JUNSHI PHARMA; see Si-Yang Liu et al, J.Hematol.201136: 2015201136 (2017), BGB-A317 (Beigene; see WO 38/35606 and US 2015/0079109), CSHR 1210; Jian 1210; Yang sui. su 84; WO 357. Oncol. 2015/085847; Hengcol. 10. H.7. Oncol., TSR-042(ANB 011; TesaroBiopharmaceutical; see WO2014/179664), GLS-010(WBP 3055; Wuxi/Harbin Gloria pharmaceuticals; see Si-Yang Liu et al, J.Hematol.Oncol.10:136(2017)), AM-0001 (armor), STI-1110(Sorrent Therapeutics; see WO 2014/194302), AGEN2034 (Agenus; see WO2017/040790), MGD013(Macrogenics) and IBI308 (Innovent; see WO2017/024465, WO2017/025016, WO 2017/132825, WO 2017/133540).
In some embodiments, the anti-PD-1 antibody is nivolumab. Nivolumab is a fully human IgG4(S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby preventing down-regulation of anti-tumor T cell function (U.S. Pat. No. 8,008,449; Wang et al, 2014Cancer immune res.2(9): 846-56).
In other embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody directed against human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1). Pembrolizumab is described, for example, in U.S. patent nos. 8,354,509 and 8,900,587; see also www.cancer.gov/drug dictionary? cdrid 695789 (last visit time: 12/14/2014). Pembrolizumab has been approved by the FDA for the treatment of relapsed or refractory melanoma.
anti-PD-1 antibodies useful in the disclosed methods also include isolated antibodies that specifically bind to human PD-1 and cross-compete with any of the anti-PD-1 antibodies disclosed herein for binding to human PD-1, such as nivolumab (see, e.g., U.S. Pat. Nos. 8,008,449 and 8,779,105; WO 2013/173223). In some embodiments, the anti-PD-1 antibody binds to the same epitope as any one of the anti-PD-1 antibodies described herein (e.g., nivolumab). The ability of antibodies to cross-compete for binding to antigen indicates that these monoclonal antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competitive antibodies are expected to have very similar functional properties to the reference antibody (e.g., nivolumab) due to their binding to the same epitope region of PD-1. Cross-competing antibodies can be readily identified in standard PD-1 binding assays such as Bicore assays, ELISA assays, or flow cytometry based on their ability to cross-compete with nivolumab (see, e.g., WO 2013/173223).
In certain embodiments, an antibody that cross-competes with the same epitope region of the human PD-1 antibody nivolumab for binding to human PD-1 or binds the same epitope region of the human PD-1 antibody nivolumab is a monoclonal antibody. For administration to a human subject, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
anti-PD-1 antibodies useful in the methods of the disclosed invention also include antigen-binding portions of the above antibodies. It is well established that the antigen binding function of an antibody can be performed by fragments of a full-length antibody.
anti-PD-1 antibodies suitable for use in the disclosed methods or compositions are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and/or PD-L2, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits similar functional properties as a whole antibody in terms of inhibiting ligand binding and upregulating the immune system. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.
Antibody B
Due to the lack of cross-reactivity of nivolumab with mouse PD-1, an anti-mouse PD-1 antibody (hereinafter antibody B) was generated by the humanization of the Fc tail of 4H2 (rat anti-mouse PD1 antibody). Antibody B comprises mouse IgG 1D 265A and comprises variable region light and heavy chain sequences as shown below.
Antibody B light chain variable region:
DTVLTQSPALAVSLGQRVTISCKASETVSSSMYSYIHWYQQKPGQQPKLLIYRASNLESGVPARFSGSGSGTDFTLTIDPVEADDVATYFCQQSWNPWTFGGGTKLELKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC(SEQID NO:1)
antibody B heavy chain variable region:
QVQLKESGPGLVQPSQTLSLTCTVSGFSLTSYNVHWVRQPPGKGLEWMGGMRYNEDTSYNSALKSRLSISRDTSKNQVFLKMNSLQTDDTGTYYCTRDAVYGGYGGWFAYWGQGTLVTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK(SEQID NO:2)
antibody B was used as an anti-PD 1 mouse surrogate to investigate the efficacy of a CCR 2/5-dual antagonist in combination with an anti-PD 1 antibody. 4H2 bound to CHO cells expressing mouse PD1 showed an EC50 of 2.9nM, which is comparable to EC50(0.4nM) of nalmeuzumab bound to CHO cells expressing human PD 1. Furthermore, 4H2 showed an IC50 of 3.6nM and 4.9nM, respectively, blocking the binding of mouse PD1 to mouse PD-L1 and mouse PD-L2, which is comparable to the IC50 of the binding of Niumamab to human PD-L1 and human PD-L2 (1.04 nM and 0.97nM, respectively) (Table 2)
TABLE 2 mouse potency of antibody B and human potency of nivolumab
Assay for direct binding of anti-PD-1 monoclonal antibody (mAb) to PD1 stably expressed on CHO transfectants
Mabs against human and mouse PD-1 were serially diluted and incubated with CHO cell transfectants stably expressing human and mouse PD-1, respectively, and then detected with FITC-conjugated secondary anti-mouse IgG Fc γ antibodies.
Assay for blocking binding of PD-L1 to PD-1 stably expressed on CHO transfectants
CHO transfectants stably expressing human and mouse PD-1 were pre-incubated with titrating mAbs to human and mouse PD-1, respectively, followed by the addition of 2. mu.g/mL PD-L1-Fc. Cell-bound PD-L1-Fc was detected with a FITC-conjugated anti-human IgG Fc γ secondary antibody.
Assay for blocking binding of PD-L2 to PD-1 stably expressed on CHO transfectants
CHO transfectants stably expressing human and mouse PD-1 were pre-incubated with titrating mAbs to human and mouse PD-1, respectively, followed by addition of 15. mu.g/ml of PD-L2-Fc. Cell-bound PD-L2-Fc was detected with a FITC-conjugated anti-human IgG Fc γ secondary antibody.
anti-PD-L1 antibodies useful in the invention
Any anti-PD-L1 antibody can be used in the methods of the present application. Examples of anti-PD-L1 antibodies useful in the methods of the present application include the antibodies disclosed in U.S. patent No. 9,580,507. Each of the anti-PD-L1 human monoclonal antibodies disclosed in U.S. patent No. 9,580,507 has been shown to exhibit one or more of the following characteristics: (a) with KDIs 1x10-7M or less binds to human PD-L1 as determined by surface plasmon resonance using a Biacore biosensor system; (b) increase in mixed lymphT cell proliferation in a cell response (MLR) assay; (c) increasing interferon- γ production in an MLR assay; (d) increasing IL-2 secretion in an MLR assay; (e) stimulating an antibody response; and (f) reversing the effects of T regulatory cells on T cell effector cells and/or dendritic cells. anti-PD-L1 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one, and in some embodiments at least five of the foregoing characteristics.
In certain embodiments, the anti-PD-L1 antibody is selected from BMS-936559 (previously 12A4 or MDX-1105; see, e.g., U.S. Pat. Nos. 7,943,743 and WO 2013/173223), MPDL3280A (also known as RG7446, attuzumab and TECENTRIQ; US 8,217,149; also see, Herbst et al (2013) J Clin Oncol 31(suppl):3000) dewar (IMFINZI; MEDI-4736; AstraZeneca; see WO 2011/066389), Avermectin (Pfizer; MSB-0010718C; BAVENTIO; see WO 2013/079174), STI-1014 (Sorrento; see WO2013/181634), CX-072 (Cytomx; see WO2016/149201), KN035(3D Med/Alphamab; see Zhang et al, Cell Discov.7:3(March 2017), LY3300054(Eli Lilly Co.; see, e.g., WO 2017/034916) and CK-301(Checkpoint Therapeutics; see Gorelik et al, AACR: absstract 4606(Apr 2016)).
In certain embodiments, the PD-L1 antibody is trastuzumab (TECENTRIQ). The trastuzumab is a fully humanized IgG1 monoclonal antibody PD-L1.
In certain embodiments, the PD-L1 antibody is de Waiumab (IMFINZI). Dewaruzumab is the human IgG1 kappa monoclonal antibody PD-L1.
In certain embodiments, the PD-L1 antibody is avizumab (BAVENCIO). The Abelmuzumab is a human IgG1 lambda monoclonal antibody PD-L1.
In other embodiments, the anti-PD-L1 monoclonal antibody is selected from the group consisting of 28-8, 28-1, 28-12, 29-8, 5H1, and any combination thereof.
anti-PD-L1 antibodies useful in the disclosed methods also include isolated antibodies that specifically bind to human PD-L1, and cross-compete with any of the anti-PD-L1 antibodies disclosed herein, e.g., trastuzumab and/or avizumab, for binding to human PD-L1. In some embodiments, the anti-PD-L1 antibody binds to the same epitope as any of the anti-PD-L1 antibodies described herein, e.g., trastuzumab and/or avizumab. The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have very similar functional properties to reference antibodies such as trastuzumab and/or avizumab due to their binding to the same epitope region of PD-L1. Cross-competing antibodies can be readily identified in standard PD-L1 binding assays, such as Biacore analysis, ELISA assays, or flow cytometry, based on their cross-competing ability with pertuzumab and/or avizumab (see, e.g., WO 2013/173223).
In certain embodiments, an antibody that cross-competes with the same epitope region of a human PD-L1 antibody, such as trastuzumab and/or avizumab, for binding to human PD-L1 or for binding to the same epitope region of a human PD-L1 antibody, such as trastuzumab and/or avizumab, is a monoclonal antibody. For administration to a human subject, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
anti-PD-L1 antibodies useful in the methods of the disclosed invention also include antigen-binding portions of the above antibodies. It is well established that the antigen binding function of an antibody can be performed by fragments of a full-length antibody.
anti-PD-L1 antibodies suitable for use in the disclosed methods or compositions are antibodies that bind to PD-L1 with high specificity and affinity, block the binding of PD-1, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits functional properties similar to those of a whole antibody in inhibiting receptor binding and upregulating the immune system. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with trastuzumab and/or avizumab for binding to human PD-L1.
anti-CTLA-4 antibodies useful in the invention
Any anti-CTLA-4 antibody known in the art can be used in the methods of the present application. The anti-CTLA-4 antibodies of the invention bind to human CTLA-4, thereby disrupting the CTLA-4 interaction with the human B7 receptor. Because CTLA-4 interacts with B7 to transduce a signal, which results in the inactivation of T cells bearing CTLA-4 receptors, disruption of the interaction effectively induces, enhances or prolongs activation of such T cells, thereby inducing, enhancing or prolonging an immune response.
In certain embodiments, the CTLA-4 antibody is selected from ipilimumab (YERVOY; U.S. Pat. No. 6,984,720), MK-1308(Merck), AGEN-1884(Agenus Inc.; WO 2016/196237), and Techilimumab (formerly ticilimumab, CP-675,206; AstraZeneca; see, e.g., WO 2000/037504 and Ribas, Updatecancer ther Ther.2(3):133-39 (2007)). In particular embodiments, the anti-CTLA-4 antibody is ipilimumab.
In particular embodiments, the CTLA-4 antibody is tremelimumab (also known as CP-675,206). The Texiletine single antibody is a human IgG2 monoclonal antibody CTLA-4. Tessimumab is described in WO/2012/122444, U.S. publication No. 2012/263677, or International publication No. 2007/113648A 2.
In a particular embodiment, the CTLA-4 antibody is MK-1308, which is an anti-CTLA-4 antibody developed by Merck.
In a particular embodiment, the CTLA-4 antibody is AGEN-1884, which is a recombinant human monoclonal antibody to human CTLA-4 developed by Agenus inc.
anti-CTLA-4 antibodies useful in the disclosed methods also include isolated antibodies that specifically bind to human CTLA-4 and cross-compete with any anti-CTLA-4 antibody disclosed herein, e.g., ipilimumab and/or tiximumab, for binding to human CTLA-4. In some embodiments, the anti-CTLA-4 antibody binds to the same epitope as any anti-CTLA-4 antibody described herein, e.g., ipilimumab and/or tiximumab. The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. It is expected that these cross-competing antibodies have very similar functional properties to reference antibodies such as ipilimumab and/or teximumab, since they bind to the same epitope region of CTLA-4. Cross-competing antibodies can be readily identified in standard CTLA-4 binding assays, such as Biacore analysis, ELISA assays, or flow cytometry, based on their ability to cross-compete with ipilimumab and/or teximumab (see, e.g., WO 2013/173223).
In certain embodiments, the antibody that cross-competes for binding to human CTLA-4 with the same epitope region of a human CTLA-4 antibody, e.g., ipilimumab and/or tixemumab, or binds to the same epitope region of a human CTLA-4 antibody, e.g., ipilimumab and/or tixemumab, is a monoclonal antibody. For administration to a human subject, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.
anti-CTLA-4 antibodies useful in the methods of the disclosed invention also include antigen-binding portions of the above antibodies. It is well established that the antigen binding function of an antibody can be performed by fragments of a full-length antibody.
anti-CTLA-4 antibodies suitable for use in the disclosed methods or compositions are antibodies that bind CTLA-4 with high specificity and affinity, block CTLA-4 activity, and disrupt CTLA-4 interaction with the human B7 receptor. In any of the compositions or methods disclosed herein, an anti-CTLA-4 "antibody" includes an antigen-binding portion or fragment that binds to CTLA-4 and exhibits functional properties similar to those of a whole antibody in inhibiting CTLA-4 interaction with a human B7 receptor and upregulating the immune system. In certain embodiments, the anti-CTLA-4 antibody or antigen-binding portion thereof cross-competes with ipilimumab and/or tixelimumab to bind to human CTLA-4.
As used herein, "combination" is meant to include therapies that can be administered alone, e.g., formulated separately for separate administration (e.g., as can be provided in a kit), as well as therapies that can be administered together in a single formulation (i.e., "co-formulation"). In certain aspects, the monoclonal antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof and/or chemotherapy are administered or administered sequentially, e.g., wherein one agent is administered prior to one or more other agents. In other embodiments, the monoclonal antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof and/or chemotherapy are administered simultaneously, e.g., wherein two or more agents are administered simultaneously or about simultaneously; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a co-formulation). Whether two or more agents are administered sequentially or simultaneously, they are considered for the purposes of this application to be administered in combination.
In an exemplary aspect of the disclosure, the antibody is nivolumab. In some aspects, nivolumab may be administered by intravenous infusion at a dose of about 400mg to 500mg every 4 weeks. For example, nivolumab may be administered to a subject by intravenous infusion at the following doses: about 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg or about 500mg every 4 weeks. In a preferred aspect, nivolumab may be administered by intravenous infusion at a dose of about 480mg every 4 weeks.
In some aspects, nivolumab may be administered to the subject by intravenous infusion at a dose of about 80mg to 360mg every 3 weeks. For example, nivolumab may be administered to a subject by intravenous infusion at the following doses: about 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg or about 360mg every 3 weeks. In a preferred aspect, nivolumab may be administered by intravenous infusion at a dose of about 80mg every 3 weeks. In other preferred aspects, nivolumab is administered by intravenous infusion at a dose of about 360mg every 3 weeks.
In some aspects, nivolumab may be administered by intravenous infusion at a dose of about 200mg to 300mg every 2 weeks. For example, nivolumab may be administered to a subject by intravenous infusion at the following doses: about 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg or about 300mg every 2 weeks. In a preferred aspect, nivolumab may be administered by intravenous infusion at a dose of about 240mg every 2 weeks.
In some aspects, nivolumab is further administered with ipilimumab, wherein ipilimumab can be administered by intravenous infusion at a dose of about 1mg/kg to 10mg/kg every 3 weeks. For example, ipilimumab may be administered to a subject by intravenous infusion at the following doses: about 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg or 10mg/kg every 3 weeks. In a preferred aspect, ipilimumab can be administered by intravenous infusion at a dose of about 3mg/kg every 3 weeks.
As used herein, "administered to a subject" and similar terms refer to the procedure of injecting a compound into a patient such that target cells, tissues or fragments of the subject's body are contacted with the compound. Methods of administration contemplated herein include, but are not limited to, oral, topical, inhalation, or parenteral administration. Suitable parenteral administration methods include, but are not limited to, intravenous, intramuscular, subcutaneous and intradermal parental administration.
In some aspects, a combination of a monoclonal antibody described herein and a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a subject having cancer, wherein the subject can have been previously administered at least one previous therapy for treating cancer. Such a subject may be referred to as "having undergone treatment" or "not having undergone treatment". In some aspects, prior therapies are in progress. In other aspects, prior therapy has been terminated. In these subjects, prior therapy may be discontinued for about 12 hours or 24 hours. In other aspects, prior therapy may be discontinued for about 2 days, 3 days, 4 days, 5 days, or 6 days. In other aspects, prior therapy may be discontinued for about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or longer. In some aspects, prior therapy may be discontinued for about 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, or about 11 months. In other aspects, prior therapy may be discontinued for about 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or about 10 years.
Examples of prior therapies include, but are not limited to: surgery, radiation therapy, chemotherapy, immunotherapy, targeted therapy, hormonal therapy, stem cell transplantation, or precision medical therapy.
As used herein, "chemotherapy" refers to the administration of one or more chemotherapeutic drugs and/or other agents to a cancer patient by various methods, including intravenous, oral, intramuscular, intraperitoneal, intravesical, subcutaneous, transdermal, buccal, inhalation, or suppository forms.
As used herein, "surgery" refers to a surgical procedure for removal of cancerous tissue, including, but not limited to, tumor biopsy or removal of part or all of the colon (colostomy), bladder (cystectomy), spleen (splenectomy), gallbladder (cholecystectomy), stomach (gastrectomy), liver (partial hepatectomy), pancreas (pancreatectomy), ovary and fallopian tube (bilateral salpingo-oophorectomy), omentum (dictyostomy), and/or uterus (hysterectomy).
In some aspects, a combination of a monoclonal antibody described herein and a compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered to a subject having cancer, wherein the subject is untreated. As used herein, "untreated" refers to a subject that has not previously been administered a previous therapy for the treatment of cancer.
In certain aspects, the monoclonal antibody and the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered in further combination with other therapeutic agents in any manner as appropriate. Examples of therapeutic agents that may be used in combination to treat the cancers disclosed herein include radiation, immunomodulators, or chemotherapeutic agents or diagnostic agents. Suitable immunomodulators which can be used in the present invention include other monoclonal antibodies described herein, CD40L, B7 and B7RP 1; monoclonal antibodies (mAbs) that activate stimulatory receptors, such as anti-CD 40, anti-CD 38, anti-ICOS and 4-IBB ligands; dendritic cell antigen loading (in vitro or in vivo); anti-cancer vaccines such as dendritic cell carcinoma vaccines; cytokines/chemokines, such as IL1, IL2, IL12, IL18, ELC/CCL19, SLC/CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa/b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial Lipopolysaccharides (LPS); and an immunostimulatory oligonucleotide.
Examples of chemotherapeutic agents include, but are not limited to, alkylating agents, such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodidopa, carboquone, meltupipa, and urepipa; ethyleneimines and methylmelamines including altretamine, tritamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards, such as chlorambucil, chlorophosphamide, estramustine, ifosfamide, dichloromethyldiethylamine, chlorfenamic acid, melphalan, neomustard, benzene mustard cholesterol, prednisme, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorouramicin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, such as aclacinomycin, actinomycin, amtriptan, azaserine, bleomycin, actinomycin C, calicheamicin, carabixin, carminomycin, carcinomycin, tryptophycetin, actinomycin D, daunorubicin, ditobicin, diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, isorubicin, idarubicin, marijuomycin, mitomycin, mycophenolic acid, norramycin, olivomycin, pelomycin, posomycin, puromycin, trirubicin, roxobicin, streptomycin, streptozotocin, tubercidin, ubenimex, setastin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluorouridine, enocitabine, and fluorouridine; androgens such as carroterone, drotaandrosterone propionate, epithioandrostanol, meiandrostane, testolactone; anti-adrenal agents, such as aminoglutethimide, mitotane, trostane; folic acid compensators, such as folinic acid; acetic acid glucurolactone; hydroxyaldehyde phosphoramide glycoside; 5-aminolevulinic acid; amsacrine; amoxicillin; a bisantrene group; edatrexae; desphosphamide; colchicine; diazaquinone; eflornithine; ammonium etiolate; etoglut; gallium nitrate; a hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidanol; nisridine; pentostatin; promethazine; pirarubicin; podophyllinic acid; 2-ethyl hydrazide; procarbazine; lezoxan; a texaphyrin; a germanium spiroamine; alternarionic acid; a tri-imine quinone; 2,2' -trichlorotriethylamine; uratan; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulcitol; pipobroman; adding cytosine; cytarabine (Ara-C); cyclophosphamide; thiotepa; taxanes, such as paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; novier; noxiaoling; (ii) teniposide; daunomycin; aminopterin; (ii) Hirodad; ibandronate; CPT 11; a topoisomerase inhibitor; difluoromethyl ornithine (DMFO); retinoic acid; an epstein-barr; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
Chemotherapeutic agents also include anti-hormonal agents that act to modulate or inhibit the action of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5) -imidazole, 4-hydroxyttamoxifen, trovaxifen, keoxifene, onapristone, and toremifene; and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy includes administration of a hormone or related hormone formulation.
Chemotherapeutic agents also include Signal Transduction Inhibitors (STI). The term "signal transduction inhibitor" refers to an agent that selectively inhibits one or more steps in a signaling pathway. The Signal Transduction Inhibitor (STI) of the present invention includes: (i) inhibitors of bcr/abl kinase (e.g., GLEEVEC)TM) (ii) a (ii) Epidermal Growth Factor (EGF) receptor inhibitors, including kinase inhibitorsFormulations and antibodies; (iii) her-2/neu receptor inhibitors (e.g., HERCEPTIN)TM) (ii) a (iv) Inhibitors of Akt family kinases or Akt transduction pathways (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., frataxin); and (vi) a phosphatidylinositol kinase inhibitor.
Chemotherapeutic agents also include oxaliplatin, vitamin B derivatives such as leucovorin (FOL, folinic acid), and topoisomerase inhibitors such as irinotecan.
In some embodiments, the chemotherapeutic agent is selected from the group consisting of paclitaxel, gemcitabine, 5-fluorouracil (5-FU), leucovorin, and irinotecan.
FOLFIRI is a chemotherapy regimen that includes FOL-folinic acid (leucovorin) and F-fluorouracil (5-FU) and IRI-irinotecan.
FOLFOX is a chemotherapy regimen that includes FOL-folinic acid (leucovorin) and F-fluorouracil (5-FU) and OX-oxaliplatin.
Gem/ABRAXANE (nab-paclitaxel) is a chemotherapy regimen that includes gemcitabine and nab-paclitaxel.
Other therapeutic modalities that can be used in combination with a monoclonal antibody and a compound of formula (I) or a pharmaceutically acceptable salt thereof include cytokines or cytokine antagonists, such as IL-12, IFN or anti-epidermal growth factor receptor, radiation therapy, a monoclonal antibody directed against another tumor antigen, a complex of a monoclonal antibody and a toxin, a T cell adjuvant, bone marrow transplantation, or antigen presenting cells (e.g., dendritic cell therapy). Vaccines (e.g., as soluble proteins or as nucleic acids encoding proteins) are also provided.
"cancer" refers to a variety of diseases characterized by uncontrolled growth of abnormal cells in the body. "cancer" or "cancerous tissue" may include tumors. Uncontrolled cell division and growth leads to the formation of malignant tumors, which invade adjacent tissues and may also metastasize to distant parts of the body via the lymphatic system or the blood stream. After metastasis, the distal tumor can be said to be "derived" from the pre-metastatic tumor. For example, "a tumor derived from pancreatic cancer" refers to a tumor due to metastatic pancreatic cancer. Because the distal tumor is derived from a pre-metastatic tumor, a "derived" tumor may also include a pre-metastatic tumor, e.g., a tumor derived from pancreatic cancer may include pancreatic cancer.
In some aspects, the cancer is a malignant solid tumor. In a further aspect, the cancer is metastatic and/or unresectable. Examples of cancers that may be treated using the compounds and compositions described herein include, but are not limited to: pancreatic cancer, colorectal cancer, non-small cell lung cancer, renal cell carcinoma; head and neck squamous cell carcinoma, bladder cancer, prostate cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal carcinoma), Mesothelial lining cancer, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including small cell lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, or skeletal cancer; glioblastoma, mesothelioma, gastric cancer, sarcoma, choriocarcinoma, basal cell carcinoma of the skin and testicular seminoma. In a preferred aspect, the cancer is cervical cancer, non-small cell lung cancer, renal cell carcinoma; head and neck squamous cell carcinoma, bladder cancer, pancreatic cancer, melanoma, lymphoma, or gastric cancer. In a more preferred aspect, the cancer is melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, bladder cancer, renal cell carcinoma, or gastric cancer.
In some aspects of the present application, the subject exhibits an improvement in her Eastern Cooperative Oncology Group (ECOG) performance status following treatment according to any of the disclosed methods. In some aspects, the subject exhibits an ECOG performance status of less than or equal to 1 following a treatment described herein. In other aspects, the subject exhibits an ECOG performance status of less than or equal to 2 after treatment. In other aspects, the subject exhibits an ECOG performance status of less than or equal to 3 after treatment. In other aspects, the subject exhibits an ECOG performance status of less than or equal to 4 after treatment. ECOG performance status developed by the eastern cooperative oncology group provides the following status descriptions in rank: the 0 level is full initiative and can perform all pre-disease manifestations without limitation; class 1 strenuous physical activity is limited, but ambulatory and capable of light or sedentary tasks, such as professional counseling room work, office work; level 3 is mobile, enabling all self-care, but not any work activities; accounting for greater than about 50% of the number of wake hours.
In some aspects, the subject is an adult. For example, the adult population may include subjects 18 years of age and older. In other aspects, the subject is an elderly subject. For example, an elderly population may include subjects 64 years of age and older. In other aspects, the subject is a pediatric subject. For example, a pediatric subject may be a preterm infant (the birth period of a newborn born prior to full gestation), a full term newborn (born to 27 days), an infant (28 days to 12 months), a toddler (13 months to 2 years), a toddler period (2 years to 5 years), a midchildhood (6 years to 11 years), an early adolescence (12 years to 18 years), or a late adolescence (19 years to 21 years).
In some aspects, the treatment methods disclosed herein can result in treatment-related adverse events (TRAEs), as established by the Universal term for adverse events Standard (CTCAE), issued by the U.S. department of health and public service. An Adverse Event (AE) is any adverse and unexpected sign (including abnormal laboratory test results), symptom or disease that is temporally related to the use of, may be considered related to or may be considered unrelated to a medical treatment or procedure. AE is a term used for the unique representation of specific events in the medical literature and scientific analysis. The general criteria for CTCAE establishment are as follows: grade refers to the severity of AE, with grade 1 defined as mild; no symptoms or mild symptoms; clinical or diagnostic only opinions; no intervention is indicated. Grade 2 is defined as medium; indicated minimal, local or non-invasive intervention; limited in age-related instrumental Activities of Daily Living (ADL). Grade 3 is severe or medically significant, but not immediately fatal; indicating admission or extending hospital stay; disability; the activities of the self-organizing daily life are limited. Level 4 is the result of the best life; indicating an emergency intervention. Grade 5 is death associated with AE. Examples of TRAEs greater than or equal to 2 include uveitis, anorexia, fever, anemia, autoimmune hepatitis, fatigue, headache, nausea, and/or vomiting. Examples of grade 3/4 TRAEs (also known as "severe TRAEs") include increased lipase, hypophosphatemia, rash, increased aspartate aminotransferase, increased alanine aminotransferase, hepatitis, hypertension, pancreatitis, and/or autoimmune hepatitis.
In certain aspects, the treatment described herein may not result in grade 4 or grade 5 adverse events. In other aspects, the treatment described herein can result in no more than a grade 1 adverse event. In a further aspect, the treatment described herein can result in no more than a grade 2 adverse event. In a still further aspect, the treatment described herein can result in no more than grade 3 adverse events.
In aspects of the methods disclosed herein, the subject may exhibit improved anti-tumor activity as measured by Objective Response Rate (ORR), duration of response, and rate of Progression Free Survival (PFS).
Objective Response Rate (ORR) can be quantified by researchers and/or physicians evaluating responses using the solid tumor Response Evaluation Criteria (RECIST) v1.1 as developed by the european organization for cancer research and treatment (EORTC), the american National Cancer Institute (NCI), and the american and canadian national cancer institute clinical trial panel. Optionally, the ORR can optionally be examined by a central imaging laboratory.
"progression-free survival (PFS)" as used in the context of cancer as described herein refers to the length of time during and after cancer treatment until objective progression or death of the tumor. Treatment can be assessed by objective or subjective parameters; including results of physical examination, neurological examination, or psychiatric evaluation. In a preferred aspect, PFS may be assessed by blinded imaging centric examination, and may further optionally be confirmed by ORR or blinded independent centric examination (BICR).
The "overall survival rate (OS)" can be assessed by OS rate at certain time points (e.g. 1 and 2 years) by the Kaplan-Meier method and the corresponding 95% CI is derived based on the Greenwood formula by studying the treatment of each tumor. The OS rate is defined as the proportion of participants that are still alive at that point in time. The OS of the participants was defined as the time from the date of the first dose to the date of death for any reason.
As used herein, an "adverse event" (AE) is any adverse and often unexpected or undesirable sign (including abnormal laboratory results), symptom or disease associated with the use of medical treatment. A medical treatment may have one or more associated adverse events, and the severity of each adverse event may be the same or different. Reference to a method that is capable of "altering an adverse event" refers to a treatment regimen that reduces the incidence and/or severity of one or more adverse events associated with the use of a different treatment regimen.
"subtherapeutic dose" refers to a dose of a therapeutic compound (e.g., an antibody) that is less than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease (e.g., cancer).
In some embodiments, the methods disclosed herein are used in place of standard of care therapy. In certain embodiments, the standard of care therapy is used in combination with any of the methods disclosed herein. Standard of care therapies for different types of cancer are well known to those skilled in the art. For example, the National Comprehensive Cancer Network (NCCN), consisting of 21 major cancer centers in the United states, promulgates the clinical practice guide for NCCN oncology (NCCN)) It provides up-to-date information on standard-of-care treatment of various cancers (see NCCN)2014, available from: www.nccn.org/professional/physics _ gls/f _ guidelines. asp, last visit time 5/14/5/2014).
Treatment is continued as long as clinical benefit is observed or until unacceptable toxicity or disease progression occurs. In certain embodiments, the anti-PD-1 antibody can be administered at a dose that has been shown to produce the highest therapeutic effect as a monotherapy in a clinical trial, for example, about 3mg/kg nivolumab, about once every three weeks (Topalian et al, 2012N Engl J Med 366: 2443-54; Topalian et al, 2012Curr Opin Immunol 24:207-12), at a flat dose of 240mg, or at a significantly lower dose, i.e., a sub-therapeutic dose.
The dose and frequency depend on the half-life of the antibody in the subject. Typically, human antibodies exhibit the longest half-life, followed by humanized, chimeric, and non-human antibodies. The dosage and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, relatively low doses are typically administered at relatively infrequent intervals over a long period of time. Some patients continue to receive treatment for the lifetime. In therapeutic applications, it is sometimes desirable to use relatively high doses at relatively short intervals until the progression of the disease is reduced or terminated, and until the patient exhibits partial or complete remission of the disease symptoms. Thereafter, a prophylactic regimen can be administered to the patient.
The actual dosage level of the active ingredient in the pharmaceutical compositions of the present application can be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without undue toxicity to the patient. The selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular composition employed in the present application, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or substances used in combination with the particular composition employed, the age, sex, body weight, condition, general health, and past medical history of the patient being treated, and like factors well known in the medical arts. The compositions of the present application can be administered via one or more routes of administration using one or more of a variety of methods well known in the art. As will be appreciated by those skilled in the art, the route and/or manner of administration will vary depending on the desired result.
Reagent kit
Also within the scope of the present application are kits comprising a dual CCR2/5 antagonist, a monoclonal antibody and/or a chemotherapeutic agent for therapeutic use. The kit typically contains a label indicating the intended use and instructions for use of the kit contents. The term label includes any written or recorded material on or with the kit or with which the kit is attached.
The following examples are illustrative only and are not intended to limit the application to the materials, conditions, or process parameters set forth therein.
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