Methods of treating cancer with antagonistic anti-PD-1 antibodies
阅读说明：本技术 用拮抗性抗-pd-1抗体治疗癌症的方法 (Methods of treating cancer with antagonistic anti-PD-1 antibodies ) 是由 E·F·阿提耶 K·贝 J·G·格力 谢洪 C·L·迈耶 于 2019-01-19 设计创作，主要内容包括：本发明涉及用拮抗性抗-PD-1抗体治疗癌症的方法、该拮抗性抗-PD-1抗体的制剂和该抗-PD-1抗体的药物产品。(The present invention relates to methods of treating cancer with antagonistic anti-PD-1 antibodies, formulations of the antagonistic anti-PD-1 antibodies, and pharmaceutical products of the anti-PD-1 antibodies.)
1. A method of treating cancer, the method comprising administering to a subject diagnosed with the cancer an antagonistic anti-PD 1 antibody or antigen binding fragment thereof at a dose between about 240mg and about 480mg, the antagonistic anti-PD 1 antibody or antigen binding fragment thereof comprising heavy chain complementarity determining region 1 of SEQ ID NO: 1(HCDR1), HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3, light chain complementarity determining region 1 of SEQ ID NO:4 (LCDR1), LCDR2 of SEQ ID NO:5, and LCDR3 of SEQ ID NO: 6.
2. The method of claim 1, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
3. The method of claim 2, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof
a) Administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks at a dose of about 240 mg;
b) administered at a dose of about 240mg once every two weeks;
c) administered at a dose of about 240mg once every three weeks;
d) administered once every four weeks at a dose of about 240 mg;
e) administered once every five weeks at a dose of about 240 mg;
f) administered at a dose of about 240mg once every six weeks;
g) administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks at a dose of about 480 mg;
h) administered at a dose of about 480mg once every two weeks;
i) administered at a dose of about 480mg once every three weeks;
j) administered once every four weeks at a dose of about 480 mg;
k) administered once every five weeks at a dose of about 480 mg; or
l) is administered at a dose of about 480mg once every six weeks.
4. The method of claim 3, wherein the cancer is a solid tumor.
5. The method of claim 4, wherein the solid tumor is an advanced solid tumor.
6. The method of claim 3, wherein the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, bladder cancer, gastrointestinal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, liver cancer, colorectal cancer (CRC), colon cancer, gallbladder cancer, biliary tract cancer, ovarian cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, endometrial cancer, Small Cell Lung Cancer (SCLC), breast cancer, pancreatic cancer, renal cell cancer, liver cancer, Merkel cell cancer, primary mediastinal B-cell lymphoma (PMBCL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBLC), multiple myeloma, glioblastoma, urothelial cancer, salivary gland cancer, mesothelioma, anal cancer, prostate cancer, basal cell carcinoma, and advanced skin squamous cell carcinoma (CSCC), or any combination thereof.
7. The method of claim 6, wherein the subject has not received PD-1 axis therapy.
8. The method of claim 6, wherein the subject has received one, two, three, or more prior therapeutic agents used to treat the cancer.
9. The method of claim 8, wherein the one, two, three, or more prior therapeutic agents used to treat the cancer is an anti-CTLA 4 antibody, ipilimumab, a BRAF/MEK inhibitor, chemotherapy, or interferon alpha, or any combination thereof.
10. The method of claim 8, wherein the subject is resistant, refractory, or both resistant and refractory to the one, two, three, or more prior therapeutic agents, or any combination thereof, used to treat the cancer.
11. The method of claim 10, wherein the one, two, three, or more prior therapeutic agents used to treat the cancer is an anti-CTLA 4 antibody, ipilimumab, a BRAF/MEK inhibitor, chemotherapy, or interferon alpha, or any combination thereof.
12. The method of claim 6, wherein the cancer is PD-L1 positive.
13. The method of claim 12, wherein the cancer is high PD-L1.
14. The method of claim 6, wherein the expression of PD-L1 in the cancer is indeterminate.
15. The method of claim 6, wherein the cancer expresses mutant BRAF.
16. The method of claim 15, wherein the mutant BRAF comprises the V600E mutation.
17. The method of claim 6, wherein the cancer expresses wild-type BRAF.
18. The method of claim 6, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof
a) Administering or providing for administration in the form of a pharmaceutical composition comprising about 10mg/ml to about 30mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5;
b) administering or providing for administration in the form of a pharmaceutical composition comprising about 10mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at a pH of 6.5;
c) administering or providing for administration in the form of a pharmaceutical composition comprising about 30mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at a pH of 6.5;
d) providing for administration as a lyophilized formulation comprising between about 90mg and about 240mg of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients;
e) providing for administration as a lyophilized formulation comprising about 90mg of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients; or
f) Providing for administration as a lyophilized formulation comprising about 240mg of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients.
19. The method of claim 18, wherein the lyophilized formulation of d), e) and/or f) comprises about 30mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA after reconstitution at a pH of 6.5.
20. The method of claim 6, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is administered by intravenous infusion.
21. The method of claim 6, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is administered by subcutaneous injection.
22. The method of claim 6, wherein the method achieves an Overall Response Rate (ORR) of at least about 15% in a group of subjects diagnosed with the cancer.
23. The method of claim 22, wherein at least about 15% of the ORR is achieved after a median treatment duration of about 1 half month or greater.
24. The method of claim 22, wherein the method achieves an ORR of at least about 19% in the group of subjects diagnosed with the cancer.
25. The method of claim 6, wherein the cancer is the non-small cell lung cancer (NSCLC).
26. The method of claim 25, wherein the method achieves an ORR of at least about 30% in a group of subjects diagnosed with NSCLC having high PD-L1, or at least about 25% in a group of subjects for which PD-L1 expression in the cancer is indeterminate.
27. The method of claim 26, wherein the method achieves an ORR of at least about 35% in the group of subjects diagnosed with NSCLC having high PD-L1.
28. The method of claim 6, wherein the cancer is the melanoma.
29. The method of claim 28, wherein the method achieves an ORR of at least about 25% in a group of subjects diagnosed with the melanoma.
30. The method of claim 29, wherein the melanoma is non-uveal melanoma.
31. The method of claim 30, wherein the method achieves an ORR of at least about 30% in a group of subjects diagnosed with the non-uveal melanoma.
32. The method of claim 6, wherein the CRC is a high microsatellite instability (MSI-H) CRC or a mismatch repair deficiency (dMMR) CRC, or a combination thereof.
33. The method of claim 32, wherein the CRC is a stage II CRC or a stage III CRC.
34. The method of claim 6, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain variable region (VH) of SEQ ID NO:7 and the light chain variable region (VL) of SEQ ID NO: 8.
35. The method of claim 34, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is an IgG1, IgG2, IgG3, or IgG4 isotype.
36. The method of claim 35, wherein the antagonist anti-PD-1 antibody comprises a heavy chain of SEQ ID No. 9 and a light chain of SEQ ID No. 10.
37. A pharmaceutical composition comprising
a) Between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
b) about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
c) about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
d) a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
e) a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
f) A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
38. The pharmaceutical composition of claim 37, wherein the lyophilized formulation of d), e) and/or f) comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at pH 6.5.
39. A pharmaceutical product comprising
a) Between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
b) about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
c) about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
d) a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
e) a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
f) A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
40. The pharmaceutical product of claim 39, wherein the lyophilized formulation of d), e) and/or f) comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at pH 6.5.
41. A pharmaceutical product for use in the treatment of cancer, the pharmaceutical product comprising
a) Between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
b) about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
c) about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
d) a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
e) a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
f) A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
42. The pharmaceutical product of claim 41, wherein the lyophilized formulation of d), e) and/or f) comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at pH 6.5.
43. The pharmaceutical product of claim 41, wherein the cancer is lung cancer, non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, bladder cancer, gastrointestinal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, liver cancer, colorectal cancer (CRC), colon cancer, gallbladder cancer, biliary tract cancer, ovarian cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, endometrial cancer, Small Cell Lung Cancer (SCLC), breast cancer, pancreatic cancer, renal cell cancer, liver cancer, Merkel cell cancer, primary mediastinal B-cell lymphoma (PMBCL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBLC), multiple myeloma, glioblastoma, urothelial cancer, salivary gland cancer, mesothelioma, anal cancer, prostate cancer, basal cell carcinoma, and advanced skin squamous cell carcinoma (CSCC), or any combination thereof.
44. A pharmaceutical product according to claim 43, wherein
a) The NSCLC is a high PD-L1 NSCLC;
b) the CRC is MSI-H CRC or dMMR CRC; or
c) The melanoma is non-uveal melanoma; or any combination thereof.
45. The pharmaceutical product of claim 41, wherein the pharmaceutical product
a) Once in two weeks at a dose of about 240 mg;
b) once in four weeks at a dose of about 480 mg; or
c) An initial dose of about 240mg followed by a second dose of about 480mg six weeks after the initial dose, and then once in four weeks at a dose of about 480 mg; or
d) The initial dose is about 240mg, followed by a second dose of about 480mg six weeks after the initial dose, and then once in two weeks at a dose of about 240 mg.
46. The drug product of claim 41, wherein the drug product is administered by intravenous administration or by subcutaneous administration, or a combination thereof.
Technical Field
The present invention relates to methods of treating cancer with antagonistic anti-PD-1 antibodies, formulations of antagonistic anti-PD-1 antibodies, and pharmaceutical products of anti-PD-1 antibodies.
Sequence listing
This application contains a sequence listing submitted via EFS-Web, the entire contents of which are incorporated herein by reference. The ASCII text file created on 18/1/2019 was named JBI5152WOPCT1_ st25.txt and was 12 kilobytes in size.
Background
The immune system is tightly controlled by a network of co-stimulatory and co-inhibitory ligands and receptors. These molecules provide secondary signals for T cell activation and provide a balanced network of positive and negative signals to maximize Immune responses against infection and tumors while limiting immunity to self (Wang et al, (2011. 3. 7. day electronic edition) J Exp Med 208(3): 577-92; Lepenies et al, (2008) Endocr Metab Immune disease Drug Targets 8: 279-288). Immune checkpoint therapy, targeting co-inhibitory pathways in T cells to promote anti-tumor immune responses, has advanced in the clinical care of cancer patients.
PD-1 is a method of inhibiting CD4 in the Tumor Microenvironment (TME)+And CD8+A negative immune checkpoint molecule for T cell function. Engagement of PD-1 with its ligands (PD-L1 and PD-L2) drives T cell anergy and exhaustion within tumors by inhibiting multiple pathways downstream of T cell receptor signaling, resulting in decreased T cell survival, growth and proliferation, impaired effector function and altered metabolism. Preclinical studies show that the PD-1 pathway blocks reversible T cell failure and stimulates anti-tumor immunity.
Although the anti-PD-1/PD-L1 antibody showed encouraging clinical responses in patients with multiple solid tumors, the response rate was still quite low, about 15% to 20% in pre-treated patients (Swaika et al, (2015) molimmumol doi:10.1016/j. mollimmm. 2015.02.009).
Therefore, there is a need for new therapeutic agents that inhibit the immunosuppressive activity of checkpoint inhibitors such as PD-1 for use in cancer immunotherapy.
Disclosure of Invention
The present invention provides a method of treating cancer, the method comprising administering to a subject diagnosed with cancer an antagonistic anti-PD 1 antibody or antigen binding fragment thereof at a dose between about 240mg and about 480mg, the antagonistic anti-PD 1 antibody or antigen binding fragment thereof comprising heavy chain
The present invention also provides a pharmaceutical composition comprising between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, at a pH of 6.5;
about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
The invention also provides a pharmaceutical product comprising between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, at a pH of 6.5;
about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
The invention also provides a pharmaceutical product for the treatment of cancer comprising between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
Drawings
Figure 1 shows the mean serum concentration (μ g/ml) of JNJ-63723283 (cetrellab) over time in subjects dosed with 80mg, 240mg, 460mg, 480mg or 800mg once every two weeks (q2w) or once every four weeks (q4w), as indicated. The number of patients administered (n) is shown in parentheses.
FIG. 2 shows JNJ-63723283 (cetrellab) in CD3 over time in subjects dosed with 240mg cetrellab q2w+Percent (%) occupancy of PD-1 receptor on circulating T cells (as indicated by the administered dosing regimen 1-39). Pre: before administration; EOI + 2H: end of infusion plus 2 hours. EOI + 1H: end of infusion plus 1 hour. EOT: and (5) ending the treatment.
FIG. 3 shows JNJ-63723283 (cetrellab) in CD3 over time in subjects dosed with 480mg cetrellab q4w+Percent (%) occupancy of PD-1 receptor on circulating T cells (as indicated by the administered dosing regimen 1-14). Pre: before administration; EOI + 2H: end of infusion plus 2 hours. EOI + 1H: end of infusion plus 1 hour. EOT: and (5) ending the treatment.
Figure 4 shows the time course of T cell activation in patients receiving 240mg (solid line) once every two weeks (Q2W) or 480mg (dotted line) JNJ-63723283 (cetrellab) once every four weeks (Q4W).
Detailed Description
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if fully set forth herein.
It is to be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. 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 invention belongs.
Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, exemplary materials and methods are described herein. In describing and claiming the present invention, the following terminology will be used.
As used in this specification and the appended claims, the singular forms "a", "an", "the" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.
The transitional terms "comprising," "consisting essentially of … …," and "consisting of … …" are intended to imply their accepted meanings in patent parlance; that is, (i) "comprising" is synonymous with "including", "containing", or "characterized by", and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) "consisting of … …" excludes any element, step, or ingredient not specified in the claims; and (iii) "consisting essentially of … …" limits the scope of the claims to the specified materials or steps "and materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. Also provided are embodiments described by the phrase "comprising" (or equivalents thereof), such as those embodiments described independently by "consisting of … …" and "consisting essentially of … …".
"antagonist" or "antagonism" refers to an anti-PD 1 antibody that inhibits at least one biological activity mediated by PD-1 ligand PD-L1 or PD-L2 when bound to PD-1. An anti-PD-1 antibody is an antagonist when at least one biological activity mediated by PD-L1 or PD-L2 is inhibited by at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% more than in the absence of the antagonist (e.g., a negative control) or when the inhibition is statistically significant compared to inhibition in the absence of the antagonist.A typical biological activity mediated by the binding of PD-L1 or PD-L2 to PD-1 is antigen-specific CD4+And/or CD8+Inhibition of T cells. Thus, antagonistic antibodies alleviate PD-L1-mediated inhibition, thereby enhancing the immune response.
"PD-1" refers to human programmed
SEQ ID NO:11
PGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL
"antibody" refers broadly to and includes immunoglobulin molecules belonging to any class of IgA, IgD, IgE, IgG and IgM, or subclasses IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4, and including kappa (kappa) and Langda (lambda) light chains. Antibodies include monoclonal antibodies, full length antibodies, antigen binding fragments, bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies, and any other modified configuration of an immunoglobulin molecule comprising an antigen binding fragment with the desired specificity. A "full-length antibody" is composed of two Heavy Chains (HC) and two Light Chains (LC) interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH 3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). VH and VL can be further subdivided into hypervariable regions, termed Complementarity Determining Regions (CDRs), with intervening Framework Regions (FRs). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR 4. Antibodies include antibodies produced using various techniques, including antibodies produced by immunized mice or rats as described herein or antibodies identified from phage or mammalian display libraries.
"Complementarity Determining Regions (CDRs)" are regions of an antibody that bind antigen. Three CDRs are present in VH (HCDR1, HCDR2, HCDR3) and three CDRs are present in VL (LCDR1, LCDR2, LCDR 3). CDRs may be defined using various delineations, such as Kabat (Wu et al, (1970) J Exp Med 132:211-50) (Kabat et al, "Sequences of proteins of immunological Interest", 5 th edition, Public Health Service, National Institutes of Health, Bethesda, Md.,1991), Chothia (Chothia et al, (1987) J Mol Biol 196:901-17), IMGT (Lefranc et al, (2003) Dev Comp Immunol 27:55-77) and AbM (Martin and Thornton, (1996) J Bmol Biol263: 800-15). The correspondence between the various delineations and the variable region numbering is described (see, e.g., Lefranc et al, (2003) Dev Comp Immunol 27: 55-77; Honegger and Pluckthun, (2001) JMolBiol 309: 657-70; International Immunogenetics (IMGT) database; Web resources, http:// www _ IMGT _ org). Available programs (such as abYsis of UCL Business PLC) can be used to delineate CDRs. As used herein, the terms "CDR," "
An "antigen-binding fragment" refers to a portion of an immunoglobulin molecule that retains the antigen-binding properties of a parent full-length antibody. Exemplary antigen-binding fragments are heavy chain complementarity determining regions (HCDR)1, 2 and/or 3, light chain complementarity determining regions (LCDR)1, 2 and/or 3, VH, VL, VH and VL, Fab, F (ab')2, Fd and Fv fragments, and domain antibodies (dabs) consisting of one VH domain or one VL domain. The VH and VL domains may be linked together via a synthetic linker to form various types of single chain antibody designs, where the VH/VL domains pair intramolecularly or intermolecularly in the case where the VH and VL domains are expressed from separate chains to form a monovalent antigen binding site, such as single chain fv (scfv) or diabody; for example, in International patent publication WO1998/44001, International patent publication WO 1988/01649; international patent publication WO 1994/13804; as described in International patent publication WO 1992/01047.
"humanized antibody" refers to antibodies in which the CDR sequences are derived from a non-human species and the framework is derived from human immunoglobulin sequences. Humanized antibodies may comprise substitutions in the framework such that the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence. An antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence is a humanized antibody. Humanized antibodies may comprise substitutions in the framework such that the framework may not be an exact copy of the expressed human immunoglobulin or human immunoglobulin germline gene sequence.
"human antibody" refers to an antibody that is optimized to have a minimal immune response when administered to a human subject. The variable regions of human antibodies are derived from human germline immunoglobulin sequences. If the antibody comprises a constant region or a portion of a constant region, the constant region is also derived from a human germline immunoglobulin sequence.
A human antibody comprises a heavy chain variable region or a light chain variable region "derived" from a human germline immunoglobulin sequence if the variable region of the human antibody is derived from a system using human germline immunoglobulin genes. Exemplary systems of this type are human immunoglobulin gene libraries displayed on phage or mammalian cells, as well as transgenic non-human animals, such as mice, rats or chickens carrying human immunoglobulin loci. Due to differences between the systems used to obtain antibodies and human immunoglobulin loci, the introduction of naturally occurring somatic mutations, intentionally introducing substitutions into the framework or CDRs, so "human antibodies" typically comprise amino acid differences compared to immunoglobulins expressed in humans. A "human antibody" typically has an amino acid sequence that is about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence encoded by a human germline immunoglobulin sequence. In some cases, a "human antibody" can comprise a consensus framework sequence derived from human framework sequence analysis, e.g., as described in (Knappik et al, (2000) JMol Biol 296: 57-86); or binding to synthetic HCDR3 in a phage-displayed human immunoglobulin gene library, e.g., as described in (Shi et al, (2010) JMolBiol 397:385-96) and international patent publication WO 2009/085462. Antibodies in which the CDRs are derived from a non-human species are not included in the definition of "human antibodies".
"monoclonal antibody" refers to a population of antibodies having a single amino acid composition in each antibody chain, except for possible well-known changes such as removal of the C-terminal lysine from the antibody heavy chain, or changes due to post-translational modifications of amino acids such as methionine oxidation or deamidation of asparagine or glutamine. Monoclonal antibodies typically specifically bind to one epitope, while bispecific or multispecific monoclonal antibodies specifically bind to two or more different epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies may be monospecific or multispecific, or monovalent, bivalent, or multivalent. Included within the term "monoclonal antibody" are bispecific antibodies.
"isolated" refers to a homogeneous population of molecules (such as synthetic polynucleotides or proteins, such as antibodies) that have been substantially separated from and/or purified from other components in the system in which the molecules are produced (such as recombinant cells), as well as proteins that have been subjected to at least one purification or isolation step. An "isolated antibody" refers to an antibody that is substantially free of other cellular material and/or chemicals, and encompasses antibodies isolated to a higher purity, such as 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.
"cancer cell" or "tumor cell" refers to a cancerous, precancerous, or transformed cell in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. However transformation may occur by infection with a transforming virus and binding of new genomic nucleic acid, uptake of exogenous nucleic acid, or it may also occur spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene. Transformation/cancer is exemplified by morphological changes in vitro, in vivo and ex vivo, cell immortalization, abnormal growth control, lesion formation, proliferation, malignancy, modulation of tumor-specific marker levels, invasion, tumor growth in a suitable animal host (such as a nude mouse, etc.) (Freshney, Culture of animal Cells: AManual of basic Technique (3 rd edition, 1994)).
"cancer" refers to a wide variety of diseases characterized by uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth results in the formation of malignant tumors that invade adjacent tissues and may also metastasize to the distal parts of the body through the lymphatic system or blood stream. "cancer" or "cancer tissue" may include tumors.
"about" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular assay, result, or embodiment, "about" means within one standard deviation, or up to a range of 5% (whichever is greater), according to common practice in the art, unless otherwise explicitly stated in the examples or elsewhere in the specification.
"subject" includes any human or non-human animal. "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, reptiles, and the like. The terms "subject" and "patient" are used interchangeably herein.
"treatment" or "treating" refers to both therapeutic treatment as well as prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the growth and/or spread of tumor cells. Beneficial or desired clinical results include reduction of symptoms, shrinkage of tumor size, diminishment of extent of disease, stable (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "treatment" may also mean an increase in survival compared to the expected survival of the subject when not receiving treatment. Individuals in need of treatment include individuals already suffering from a condition or disorder as well as individuals susceptible to a condition or disorder or individuals in whom a condition or disorder is to be prevented.
"therapeutically effective amount" means an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. The therapeutically effective amount may vary depending on the following factors: such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improving the health of a patient.
An "anti-PD-1 antibody" refers to an antibody that specifically binds PD-1.
"specifically binds," "specifically binds," or "binds" refers to an antibody that binds to an antigen (e.g., PD-1) or an epitope within an antigen with a higher affinity than to other antigens-8M or less (e.g., about 1 × 10)- 9M or less, about 1 × 10-10M or less, about 1 × 10-11M or less, or about 1 × 10-12M or less) equilibrium dissociation constant (K)D) Binding to or within an antigen, usually KDK for binding of the antibody to a non-specific antigen (e.g. BSA, casein)DAt least one hundredth of. K can be measured using standard proceduresD. However, antibodies that specifically bind to an antigen or an epitope within an antigen may have cross-reactivity to other relevant antigens, e.g. to the same antigen from other species (homologues), such as humans or monkeys, e.g. cynomolgus macaque (Macaca fascicularis) (cynomolgus, cyno), chimpanzee (Pan troglodytes) (chimpanzee, chimp) or marmoset (calithrix jacchus) (common marmoset).
"dosing regimen" refers to information on the amount of therapeutic agent to be administered to a subject and the frequency of times that the subject has administered the therapeutic agent.
"dosage" refers to the amount or quantity of therapeutic agent to be administered per time.
By "recurrence" is meant the recurrence of the disease or signs and symptoms of the disease after a period of improvement following prior treatment with a therapeutic agent.
"refractory" refers to a disease that does not respond to treatment. Refractory diseases can be resistant to treatment before or at the beginning of treatment, or refractory diseases can become resistant during treatment.
"drug substance" or "DS" refers to any substance or mixture of substances intended for use in the manufacture of a pharmaceutical (medical) product, and which, when used in the production of a drug, becomes the active ingredient of the pharmaceutical product. Such substances are intended to provide pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or function of the body.
By "pharmaceutical product" or "DP" is meant a finished dosage form, such as a tablet, capsule or solution, containing an active pharmaceutical ingredient (e.g., a drug substance), which is typically, but not necessarily, associated with a non-active ingredient.
"wild-type BRAF" refers to the serine/threonine protein kinase B-raf having the amino acid sequence shown in UniProt accession No. P15056.
"mutant" refers to a polypeptide or polynucleotide that differs from a reference polypeptide or reference polynucleotide by one or more modifications (e.g., one or more substitutions, insertions, or deletions). For example, a reference BRAF polypeptide is a wild-type BRAF. Mutations are indicated using well known numbering systems, e.g. V600E refers to the substitution of glutamic acid for valine at position 600.
An "immune disorder" or "immune disorder" encompasses, for example, pathological inflammation, inflammatory disorders, and autoimmune disorders or diseases. "immune disorders" also refers to infections, persistent infections, and proliferative disorders such as cancer, tumors, and angiogenesis, including infections, tumors, and cancers that resist eradication by the immune system.
The present invention provides a method of treating cancer, comprising providing an
The present invention also provides a method of treating an immune disorder, comprising providing an
In some embodiments, the immune disorder is cancer.
In some embodiments, the immune disorder is a viral infection, a persistent viral infection, an inflammation, an inflammatory disorder, or an autoimmune disorder or disease.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 80mg, about 160mg, about 240mg, about 320mg, about 400mg, about 480mg, about 560mg, about 720mg, about 800mg, about 880mg, or about 960mg once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
The present invention also provides a method of treating cancer, the method comprising administering to a subject diagnosed with cancer an
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
The invention also provides a method of treating an immune disorder, the method comprising administering to a subject diagnosed with an immune disorder an
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 240mg once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 240mg once every two weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 240mg once every three weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 240mg once every four weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 240mg once every five weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 240mg once every six weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 480mg once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 480mg once every two weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 480mg once every three weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 480mg once every four weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 480mg once every five weeks.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 480mg once every six weeks.
Diagnosis and staging of cancer is performed by oncologists using established diagnostic criteria.
In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is an advanced solid tumor. "advanced solid tumor" refers to metastatic, unresectable stage III or stage IV solid tumors.
In some embodiments, the cancer is selected from lung cancer, non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, bladder cancer, gastrointestinal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, liver cancer, colorectal cancer (CRC), colon cancer, gallbladder cancer, biliary tract cancer, bladder cancer, ovarian cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, endometrial cancer, Small Cell Lung Cancer (SCLC), breast cancer, pancreatic cancer, renal cell cancer, liver cancer, Merkel cell cancer, primary mediastinal B-cell lymphoma (PMBCL), hodgkin's lymphoma, non-hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBLC), multiple myeloma, glioblastoma, urothelial cancer, salivary gland cancer, mesothelioma, anal cancer, prostate cancer, basal cell carcinoma, and advanced skin squamous cell carcinoma (CSCC), or any combination thereof.
In some embodiments, the cancer is selected from thymus, non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC), melanoma, bladder, kidney, stomach, esophagus, or colorectal cancer (CRC).
In some embodiments, the cancer is lung cancer.
In some embodiments, the cancer is NSCLC
In some embodiments, the cancer is melanoma.
In some embodiments, the cancer is a head and neck cancer.
In some embodiments, the cancer is bladder cancer.
In some embodiments, the cancer is a gastrointestinal cancer.
In some embodiments, the cancer is gastric cancer.
In some embodiments, the cancer is a gastroesophageal junction cancer.
In some embodiments, the cancer is esophageal cancer.
In some embodiments, the cancer is liver cancer.
In some embodiments, the cancer is CRC.
In some embodiments, the cancer is colon cancer.
In some embodiments, the cancer is gallbladder cancer.
In some embodiments, the cancer is biliary tract cancer.
In some embodiments, the cancer is ovarian cancer.
In some embodiments, the cancer is fallopian tube cancer.
In some embodiments, the cancer is cervical cancer.
In some embodiments, the cancer is peritoneal cancer.
In some embodiments, the cancer is endometrial cancer.
In some embodiments, the cancer is SCLC.
In some embodiments, the cancer is breast cancer.
In some embodiments, the cancer is pancreatic cancer.
In some embodiments, the cancer is renal cell carcinoma.
In some embodiments, the cancer is Merkel cell carcinoma.
In some embodiments, the cancer is PMBCL.
In some embodiments, the cancer is hodgkin's lymphoma.
In some embodiments, the cancer is non-hodgkin's lymphoma.
In some embodiments, the cancer is DLBLC.
In some embodiments, the cancer is multiple myeloma.
In some embodiments, the cancer is glioblastoma.
In some embodiments, the cancer is urothelial cancer.
In some embodiments, the cancer is salivary gland cancer.
In some embodiments, the cancer is mesothelioma.
In some embodiments, the cancer is anal cancer.
In some embodiments, the cancer is prostate cancer.
In some embodiments, the cancer is adenocarcinoma.
In some embodiments, the prostate cancer is metastatic prostate cancer.
In some embodiments, the prostate cancer has metastasized to the rectum, lymph nodes, or bone, or any combination thereof.
In some embodiments, the prostate cancer is relapsed or refractory prostate cancer.
In some embodiments, the prostate cancer is castration-resistant prostate cancer.
In some embodiments, the prostate cancer is sensitive to androgen-blockade therapy.
In some embodiments, the prostate cancer is not sensitive to androgen-blockade therapy.
In some embodiments, the cancer is CSCC.
In some embodiments, the cancer is a basal cell carcinoma.
In some embodiments, the cancer is a thymus carcinoma.
The present invention also provides a method of treating cancer, comprising administering to a subject diagnosed with cancer an
The invention also provides a method of treating cancer, comprising administering to a subject diagnosed with cancer an
The present invention also provides a method of treating cancer, comprising administering to a subject diagnosed with cancer an
The invention also provides a method of treating cancer, comprising administering to a subject diagnosed with cancer an
The invention also provides a method of treating cancer, comprising administering to a subject diagnosed with cancer an
By "not receiving PD-1 axis therapy" is meant a subject not treated with PD-1, PD-L1, or PD-L2 antagonists. An exemplary PD-1, PD-L1 or PD-L2 antagonist is nivolumab
In some embodiments, the cancer is PD-L1 positive.
In some embodiments, the cancer is high PD-L1.
In some embodiments, the expression of PD-L1 in a cancer is indeterminate.
"PD-L1 positive" refers to a tumor in which at least about 1% of the cells in a sample obtained from the tumor (such as a paraffin-embedded formalin-fixed tumor tissue sample) are comprised of tumor cells that stain positive for PD-L1 surface expression and tumor-infiltrating inflammatory cells.
"high PD-L1" refers to a tumor in which at least 50% of the tumor cells or tumor-infiltrating inflammatory cells in a sample obtained from the tumor (such as a paraffin-embedded formalin-fixed tumor tissue sample) stain positive for PD-L1 surface expression. Commercial kits from, for example, Ventana, DAKO, or PharmDx, can be used to assess PD-L1 positive or high PD-L1 status. In these assays, the expression of PD-L1 on tumor cell membranes was evaluated using anti-PD-L1 antibodies such as 28-8, 22C3, SP142, SP263, and 73-10, and a Tumor Proportion Score (TPS) was calculated indicating the percentage of PD-L1 positive tumor cells.
By "expression of PD-L1 in cancer is undetermined" is meant a tumor in which PD-L1 surface expression has not been assessed.
In some embodiments, the cancer expresses mutant BRAF.
In some embodiments, the mutant BRAF comprises the V600E mutation.
In some embodiments, the cancer expresses wild-type BRAF.
In some embodiments, the mutant BRAF comprises one or more mutations selected from the group consisting of: V600E, V600L, R462I, 1463S, G464E, G464R, G464V, G466A, G469A, N581S, E586K, F595L, L597Q, L597R, L597S, L597V, a598V, T599E, V600R, K601E, S602D and a728V, and any combination thereof (see, for example, international patent publication WO 2018/213302).
Mitogen-activated protein kinase (MAPK) or RAS/RAF/MEK/ERK signaling involves several cellular signal transduction pathways involved in the control of proliferation, differentiation and apoptosis. Activating mutations in the serine-threonine kinase BRAF gene are the most common genetic alterations in melanoma; BRAF mutations are observed in about 50% of cases of cutaneous melanoma and about 10% -20% of cases of mucosal melanoma (MacKiewicz and Mackiewicz, Contem Oncol 22:68-72,2018). Treatment of patients carrying BRAF mutations with BRAF inhibitors (such as vemurafenib, dabrafenib, and cornefenib) is associated with acquired resistance to treatment, and thus MEK inhibitors such as cobicistinib, trametinib, or bimetinib may be combined with a treatment regimen. MEK inhibitors have also been tested as monotherapies in subjects with BRAF mutations.
BRAF status can be assessed, for example, from tumor biopsy samples using known methods such as sequencing.
In some embodiments, the subject has received or is unable to receive at least one prior therapeutic agent used to treat cancer.
In some embodiments, the subject has received one, two, three, or more prior therapeutic agents used to treat cancer.
Therapeutic agents used to treat various cancers are known and include surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, targeted therapy, or any combination thereof.
Therapeutic agents for treating lung cancer such as non-small cell lung cancer (NSCLC) or Small Cell Lung Cancer (SCLC) include methotrexate, paclitaxelAfatinib
Therapeutic agents for the treatment of melanoma include aldesleukin, cobitinibDabrafenibDacarbazine (DTIC-
Therapeutic agents used to treat bladder cancer include surgery, chemotherapy (such as cisplatin, gemcitabine, carboplatin, methotrexate, vinblastine, doxorubicin, or any combination thereof), immunotherapy (such as attenuated bacille calmette-guerin (BCG), interferon, attrituximab
Therapeutic agents used to treat gastric cancer include surgery or chemotherapy (such as 5-fluorouracil or capecitabine, irinotecan, docetaxel or paclitaxel, or any combination thereof). Therapeutic agents used to treat esophageal cancer include surgery, endoscopic therapy, radiation therapy, chemotherapy, or targeted immunotherapy.
Therapeutic agents for the treatment of colorectal cancer (CRC) include 5-fluorouracil and leucovorin, capecitabine
Therapeutic agents used to treat thymus cancer include surgery, radiation therapy, chemotherapy (such as carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, ifosfamide, octreotide, paclitaxel, or pemetrexed, or any combination thereof), or hormonal therapy (such as corticosteroids).
Radiation therapy includes external irradiation, Intensity Modulated Radiation Therapy (IMRT), focused radiation, and any form of radiosurgery including gamma knife, radio knife, linear accelerator, and interstitial radiation (e.g., implantation of radioactive seeds, GliaSite balloons) and/or in conjunction with surgery.
Useful focused radiation methods include stereotactic radiosurgery, fractionated stereotactic radiosurgery, and Intensity Modulated Radiation Therapy (IMRT). It is apparent that stereotactic radiosurgery involves the precise delivery of radiation to tumor tissue while avoiding surrounding non-tumor normal tissue. The radiation dose delivered using stereotactic radiosurgery can vary, typically from 1Gy to about 30Gy, and can encompass intermediate ranges, including, for example, doses from 1Gy to 5Gy, 10Gy, 15Gy, 20Gy, 25Gy, up to 30 Gy. Because of the non-invasive fixation device, stereotactic radiation need not be delivered in a single treatment. The treatment plan may be reliably repeated daily, allowing multiple fractionated radiation doses to be delivered. When used to treat tumors over time, radiosurgery is referred to as "fractionated stereotactic radiosurgery" or FSR. In contrast, stereotactic radiosurgery refers to a one-time treatment. Fractionated stereotactic radiosurgery can result in a high treatment ratio, i.e., a high rate of tumor cell killing and low impact on normal tissues. Tumor and normal tissues respond differently to a single high radiation dose and multiple smaller radiation doses. A single large radiation dose can kill more normal tissue than several smaller radiation doses. Thus, multiple smaller radiation doses can kill more tumor cells while sparing normal tissues. The radiation dose delivered using fractionated stereotactic radiation can vary, ranging from 1Gy to about 50Gy, and can encompass intermediate ranges including, for example, fractional doses of 1Gy to 5Gy, 10Gy, 15Gy, 20Gy, 25Gy, 30Gy, 40Gy, up to 50 Gy. Intensity Modulated Radiation Therapy (IMRT) may also be used. IMRT is an advanced high-precision three-dimensional conformal radiotherapy (3DCRT) modality that delivers precise radiation doses to a malignant tumor or specific region within a tumor using a computer-controlled linear accelerator, using a multi-leaf collimator (MLC), the profile of each radiation beam is shaped to match the profile of the target from the perspective of the Beam (BEV), producing multiple beams. IMRT allows a more accurate adaptation of the radiation dose to the three-dimensional (3-D) shape of the tumor by adjusting the intensity of the radiation beam in multiple cells. Thus, IMRT allows a higher radiation dose to be concentrated to regions within the tumor while minimizing the dose of surrounding normal critical structures. IMRT improves the ability to adapt the treatment area to the shape of the concave tumor, for example when the tumor surrounds a vulnerable structure such as the spinal cord or major organs or blood vessels. Suitable radiation sources for use as cell modulators include both solids and liquids.
In some embodiments, one, two, three or more previous therapeutic agents used to treat cancer are anti-CTLA 4 antibodies, ipilimumab
"BRAF/MEK inhibitor" refers to a molecule, such as a small molecule, that inhibits at least one biological activity mediated by BRAF and/or MEK. In the absence of inhibitor (e.g., a negative control), or when inhibition is statistically significant compared to a control, inhibition can exceed at least about 20%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Typical biological activities mediated by BRAF and/or MEK are protein phosphorylation, cell proliferation, cell survival and apoptosis, which can be measured using standard methods.
An exemplary BRAF inhibitor is vemurafenib
An exemplary MEK inhibitor is cobitinibTrametinibAnd bimatinib.
In some embodiments, the subject is resistant, refractory, or both to one, two, three, or more prior therapeutic agents, or any combination thereof, used to treat cancer.
In some embodiments, the subject is resistant, refractory, or both to anti-CTLA 4 antibody, ipilimumab, a BRAF/MEK inhibitor, chemotherapy, or interferon alpha, or any combination thereof.
Various qualitative and/or quantitative methods can be used to determine the relapsed or refractory nature of a disease. Symptoms that may be associated with relapse or resistance are, for example, a decline or a plateau in the patient's health status, or a reestablishment or worsening of various symptoms associated with solid tumors, and/or the spread of cancer cells from one site to other organs, tissues, or cells in the body.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered or provided for administration in the form of a pharmaceutical composition comprising from about 10mg/ml to about 30mg/ml of the antagonistic anti-PD-1 antibody or antigen binding fragment thereof and one or more pharmaceutically acceptable excipients.
"pharmaceutically acceptable excipient" refers to physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, such as salts, buffers, antioxidants, sugars, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifiers, or combinations thereof.
Exemplary buffers that can be used are acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffer, HEPPSO and HEPES.
Exemplary antioxidants that can be used are ascorbic acid, methionine, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, and tartaric acid.
Exemplary amino acids that can be used are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, trileucine, alanine, glutamic acid, L-threonine, and 2-phenylalanine.
Exemplary surfactants that can be used are polysorbates (e.g., polysorbate-20 or polysorbate-80); poloxamers (e.g., poloxamer 188); triton; sodium octyl glucoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, tetradecyl-, linoleyl-or stearyl-sarcosine; linoleyl-, tetradecyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristoamidopropyl-, palmitoamidopropyl- (palmidopropyl) -, or isostearamidopropyl-betaine (e.g. lauroamidopropyl); myristamidopropyl-, palmitoylaminopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl taurate or disodium methyl oleyl taurate; and MONAQUATMSeries (Mona industries, Inc., Paterson, N.J.), polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., PLURONICS)TMPF68, etc.).
Exemplary preservatives that can be used are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrate, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkyl parabens (methyl, ethyl, propyl, butyl, etc.), alkylbenzyldimethylammonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof.
Exemplary sugars that can be used are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerol, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol isomaltulose.
Exemplary salts that can be used are acid addition salts and base addition salts. Acid addition salts include those derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous, and the like, as well as those derived from non-toxic organic acids such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include those derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, as well as those derived from non-toxic organic amines such as N, N' -dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. An exemplary salt is sodium chloride.
The amount of pharmaceutically acceptable carrier in a pharmaceutical composition can be determined experimentally based on the activity of the carrier and the desired formulation characteristics (e.g., stability and/or minimal oxidation).
In some embodiments, the pharmaceutical composition comprises histidine.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 1mM to about 50 mM.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 5mM to about 50 mM.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 5mM to about 30 mM.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 5mM to about 20 mM.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 5mM to about 15 mM.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 5mM to about 10 mM.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 1mM, about 2mM, about 3mM, about 4mM, about 5mM, about 6mM, about 7mM, about 8mM, about 9mM, about 10mM, about 11mM, about 12mM, about 13mM, about 14mM, about 15mM, about 16mM, about 17mM, about 18mM, about 19mM, about 20mM, about 21mM, about 22mM, about 23mM, about 24mM, about 25mM, about 26mM, about 27mM, about 28mM, about 29mM, about 30mM, about 31mM, about 32mM, about 33mM, about 34mM, about 35mM, about 36mM, about 37mM, about 38mM, about 39mM, about 40mM, about 41mM, about 42mM, about 43mM, about 44mM, about 45mM, about 46mM, about 47mM, about 48mM, about 49mM, or about 50 mM.
In some embodiments, the pharmaceutical composition comprises histidine at a concentration of about 10 mM.
In some embodiments, the pharmaceutical composition comprises sucrose.
In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 1% (w/v) to about 20% (w/v).
In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 2% (w/v) to about 18% (w/v).
In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 4% (w/v) to about 16% (w/v).
In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 6% (w/v) to about 14% (w/v).
In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 6% (w/v) to about 12% (w/v).
In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 6% (w/v) to about 10% (w/v).
In some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 1% (w/v), about 2% (w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v), about 8% (w/v), about 9% (w/v), about 10% (w/v), about 11% (w/v), about 12% (w/v), about 13% (w/v), about 14% (w/v), about 15% (w/v), about 16% (w/v), about 17% (w/v), about 18% (w/v), about 19% (w/v), or about 20% (w/v), in some embodiments, the pharmaceutical composition comprises sucrose at a concentration of about 8% (w/v).
In some embodiments, the pharmaceutical composition comprises polysorbate-20.
In some embodiments, the pharmaceutical composition comprises polysorbate-20 (PS-20) at a concentration of about 0.01% (w/v) to about 0.1% (w/v).
In some embodiments, the pharmaceutical composition comprises polysorbate-20 (PS-20) at a concentration of about 0.01% (w/v) to about 0.08% (w/v).
In some embodiments, the pharmaceutical composition comprises polysorbate-20 (PS-20) at a concentration of about 0.02% (w/v) to about 0.06% (w/v).
In some embodiments, the pharmaceutical composition comprises polysorbate-20 (PS-20) at a concentration of about 0.01% (w/v), about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06% (w/v), about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v), or about 0.1% (w/v).
In some embodiments, the pharmaceutical composition comprises polysorbate-20 (PS-20) at a concentration of about 0.04% (w/v).
In some embodiments, the pharmaceutical composition comprises EDTA.
In some embodiments, the pharmaceutical composition comprises EDTA at a concentration of about 1 μ g/ml to about 50 μ g/ml.
In some embodiments, the pharmaceutical composition comprises EDTA at a concentration of about 5 μ g/ml to about 50 μ g/ml.
In some embodiments, the pharmaceutical composition comprises EDTA at a concentration of about 5 μ g/ml to about 30 μ g/ml.
In some embodiments, the pharmaceutical composition comprises EDTA at a concentration of about 5 μ g/ml to about 20 μ g/ml.
In some embodiments, the pharmaceutical composition comprises EDTA at a concentration of about 5 μ g/ml to about 15 μ g/ml.
In some embodiments, the pharmaceutical composition comprises EDTA at a concentration of about 5 μ g/ml to about 10 μ g/ml.
In some embodiments, the pharmaceutical composition comprises a concentration of about 1 μ g/ml, about 2 μ g/ml, about 3 μ g/ml, about 4 μ g/ml, about 5 μ g/ml, about 6 μ g/ml, about 7 μ g/ml, about 8 μ g/ml, about 9 μ g/ml, about 10 μ g/ml, about 11 μ g/ml, about 12 μ g/ml, about 13 μ g/ml, about 14 μ g/ml, about 15 μ g/ml, about 16 μ g/ml, about 17 μ g/ml, about 18 μ g/ml, about 19 μ g/ml, about 20 μ g/ml, about 21 μ g/ml, about 22 μ g/ml, about 23 μ g/ml, about 24 μ g/ml, about 25 μ g/ml, about 26 μ g/ml, about 27 μ g/ml, or, About 28. mu.g/ml, about 29. mu.g/ml, about 30. mu.g/ml, about 31. mu.g/ml, about 32. mu.g/ml, about 33. mu.g/ml, about 34. mu.g/ml, about 35. mu.g/ml, about 36. mu.g/ml, about 37. mu.g/ml, about 38. mu.g/ml, about 39. mu.g/ml, about 40. mu.g/ml, about 41. mu.g/ml, about 42. mu.g/ml, about 43. mu.g/ml, about 44. mu.g/ml, about 45. mu.g/ml, about 46. mu.g/ml, about 47. mu.g/ml, about 48. mu.g/ml, about 49. mu.g/ml or about 50. mu.g/ml of EDTA.
In some embodiments, the pharmaceutical composition comprises EDTA at a concentration of about 20 μ g/ml.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof is administered or provided for administration in the form of a pharmaceutical composition comprising about 10mg/ml to about 30mg/ml of the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof, histidine, sucrose, polysorbate-20, and EDTA.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof is administered or provided for administration in the form of a pharmaceutical composition comprising about 10mg/ml to about 30mg/ml of the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at a pH of 6.5.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered or provided for administration in the form of a pharmaceutical composition comprising about 10mg/ml of the antagonistic anti-PD-1 antibody or antigen binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered or provided for administration in the form of a pharmaceutical composition comprising about 30mg/ml of the antagonistic anti-PD-1 antibody or antigen binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is provided for administration as a lyophilized formulation comprising between about 90mg and about 240mg of the antagonistic anti-PD-1 antibody or antigen binding fragment thereof and one or more pharmaceutically acceptable excipients.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is provided for administration as a lyophilized formulation comprising about 90mg of the antagonistic anti-PD-1 antibody or antigen binding fragment thereof and one or more pharmaceutically acceptable excipients.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is provided for administration as a lyophilized formulation comprising about 240mg of the antagonistic anti-PD-1 antibody or antigen binding fragment thereof and one or more pharmaceutically acceptable excipients.
In some embodiments, the lyophilized formulation comprises about 30mg/ml of the antagonistic anti-PD-1 antibody or antigen binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA after reconstitution at a pH of 6.5.
In some embodiments, the pharmaceutical composition is a liquid.
In some embodiments, the pharmaceutical composition is a frozen liquid.
In some embodiments, the pharmaceutical composition is a lyophilized powder.
In some embodiments, the pharmaceutical composition is provided in a volume of about 1ml to about 20 ml.
In some embodiments, the pharmaceutical composition is provided in a volume of about 1ml, about 2ml, about 3ml, about 4ml, about 5ml, about 6ml, about 7ml, about 8ml, about 9ml, about 10ml, about 11ml, about 12ml, about 13ml, about 14ml, about 15ml, about 16ml, about 17ml, about 18ml, about 19ml, or about 20 ml.
In some embodiments, the pharmaceutical composition is provided or reconstituted in a volume of about 3 ml.
In some embodiments, the pharmaceutical composition is provided or reconstituted in a volume of about 3.3 ml.
In some embodiments, the pharmaceutical composition is provided or reconstituted in a volume of about 8 ml.
In some embodiments, the pharmaceutical composition is provided or reconstituted in a volume of about 8.6 ml.
In some embodiments, the pharmaceutical composition is provided or reconstituted in a volume of about 8.8 ml.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof is administered or provided for administration in the form of a pharmaceutical composition comprising about 10mg/ml of the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof in a volume of about 3.3ml, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5.
In some embodiments, the antagonistic anti-PD-1 antibody is cetrellab. The cetrellab is an IgG 4/kappa antibody characterized by the following amino acid sequence: HCDR1 of SEQ ID NO. 1, HCDR2 of SEQ ID NO. 2, HCDR3 of SEQ ID NO. 3, LCDR1 of SEQ ID NO. 4, LCDR2 of SEQ ID NO. 5, LCDR6 of SEQ ID NO. 6, VH of SEQ ID NO. 7, VL of SEQ ID NO. 8, HC of SEQ ID NO. 9 and LC of SEQ ID NO. 10.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof is administered as or provided for administration as a lyophilized formulation comprising about 90mg of the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients, which upon reconstitution into about 3.3ml comprises about 30mg/ml of the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5.
In some embodiments, the antagonistic anti-PD-1 antibody is cetrellab.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof is administered as or provided for administration as a lyophilized formulation comprising about 240mg of the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients, which upon reconstitution into about 8.6ml comprises about 30mg/ml of the antagonistic anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5.
In some embodiments, the antagonistic anti-PD-1 antibody is cetrellab.
"lyophilization," "lyophilized," and "freeze-dried" refer to the process of first freezing the material to be dried, and then removing the ice or freezing the solvent by sublimation in a vacuum environment. Excipients may be included in the pre-lyophilized formulation to enhance the stability of the lyophilized product upon storage.
By "reconstituting" or "reconstituted" is meant dissolving the lyophilized formulation in a diluent such that the protein in the lyophilized formulation is dispersed in the reconstituted formulation. The reconstituted formulation is suitable for administration (e.g., parenteral administration), and may optionally be suitable for subcutaneous administration. In some embodiments, the diluent is sterile water for injection (sffi).
By "pharmaceutical composition", "pharmaceutical formulation" or "formulation" is meant the active ingredient (e.g., anti-PD-1 antibody) in combination with one or more excipients in liquid or solid (e.g., lyophilized) form.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered by intravenous infusion.
In some embodiments, the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is diluted to a volume of between about 100ml and 1000ml prior to administration.
In some embodiments, the duration of the intravenous infusion is between about 20 minutes and about 80 minutes.
In some embodiments, the duration of the intravenous infusion is about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, or about 80 minutes.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is administered by one or more subcutaneous injections.
The invention also provides a method of treating cancer, the method comprising administering to a subject diagnosed with cancer an
In some embodiments, the method achieves an Overall Response Rate (ORR) of at least 15% in a group of subjects diagnosed with cancer. ORR is defined as the percentage of subjects who achieved Partial Remission (PR) or Complete Remission (CR). ORR can be assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or according to irRC (irRC-Wolchok et al, (2009) in Clin cancer res 15:7412-20 immune-related response criteria) in subjects with selected advanced solid tumors.
In some embodiments, an ORR of at least about 15% is achieved after a median duration of treatment of about 1 half month or longer.
In some embodiments, at least about 15% ORR is achieved after a median treatment duration of about 1 month or more, about 2 months or more, about 3 months or more, about 4 months or more, about 5 months or more, about 6 months or more, about 7 months or more, about 8 months or more, about 9 months or more, about 10 months or more, about 11 months or more, or about 12 months or more.
In some embodiments, the method achieves an ORR of at least about 19% in a group of subjects diagnosed with cancer.
In some embodiments, the cancer is NSCLC.
In some embodiments, the method achieves an ORR of at least about 30% in a group of subjects diagnosed with NSCLC having high PD-L1, or at least about 25% in a group of subjects in which PD-L1 expression in cancer is indeterminate.
In some embodiments, the method achieves an ORR of at least about 35% in a group of subjects diagnosed with NSCLC having high PD-L1.
In some embodiments, the cancer is melanoma.
In some embodiments, the method achieves an ORR of at least about 25% in a group of subjects diagnosed with melanoma.
In some embodiments, the melanoma is non-uveal melanoma.
In some embodiments, the method achieves an ORR of at least about 30% in a group of subjects diagnosed with non-uveal melanoma.
In some embodiments, the method achieves an ORR of at least about 35% in a group of subjects diagnosed with MSI-H CRC.
In some embodiments, the method achieves an ORR of at least about 35% in a group of subjects diagnosed with dMMR CRC.
The present invention also provides a method of treating colorectal cancer (CRC), the method comprising administering to a subject diagnosed with CRC an
The invention also provides a method of treating mismatch repair deficient (dmr) colorectal cancer (CRC) or high level microsatellite instability (MSI-H) CRC, the method comprising administering to a subject diagnosed with dMMR CRC or MSI-H CRC an
Approximately 15% of colorectal cancers (CRC) have a DNA mismatch repair deficiency (dMMR), characterized by microsatellite instability (MSI) in tumors. Tumors with dMMR/MSI are usually produced by germline mutations in one of the MMR genes or by somatic inactivation of the same pathway. The dMMR/MSI tumors included hereditary nonpolyposis colorectal cancer (HNPCC) (also known as Lynch syndrome) and sporadic MSI-H CRC. Lynch syndrome is caused by germline mutations in MMR genes MLH1, MSH2, MSH6 or PMS2, or epigenetic inactivation of MSH 2. Sporadic MSI-H CRC is usually caused by methylation of the MLH1 promoter. The subset of MSI-H tumors is not altered in the MMR gene itself, but instead overexpresses various mirnas that can silence the MMR gene. For example, miRNA-21 overexpressed in MSI-H CRC was found to target MSH2 and MSH6 mRNA.
MSI-H CRC can be detected using Polymerase Chain Reaction (PCR) of tumor tissue samples for detection of microsatellite marker stability. If at least 5 markers were evaluated and instability was shown in 30% or more of the microsatellite markers, the CRC was classified as MSI-H. The National Cancer Institute (National Cancer Institute) has recommended a set of 5 microsatellites for MSI screening: BAT25 and BAT26 (single nucleotide repeats), D2S123, D5S346 and D17S250 (dinucleotide repeats). dMMR can be detected using immunohistochemistry of tumor tissue. CRC is classified as dMMR if a loss of at least one MMR gene MLH1, MSH2, MSH6 or PMS2 is detected in the tumor tissue.
In some embodiments, the CRC is a stage II CRC or a stage III CRC. CRC staging is known, for example, using the American Joint Committee for Cancer (AJCC) TNM system and diagnosed by oncologists.
In some embodiments, a subject diagnosed with CRC is refractory to treatment with fluoropyrimidine, oxaliplatin, or irinotecan, or any combination thereof.
In some embodiments, a subject diagnosed with CRC has a recurrent tumor after treatment with fluoropyrimidine, oxaliplatin, or irinotecan, or any combination thereof.
Various qualitative and/or quantitative methods can be used to determine the relapsed or refractory nature of a disease. Symptoms that may be associated with a relapsed or refractory disease are, for example, a decline or a plateau in the patient's health status, or the reconstitution or worsening of various symptoms associated with a tumor and/or the spread of cancer cells from one site to other organs, tissues or cells in the body.
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, comprising administering to a subject diagnosed with a thymus cancer an
The invention also provides a method of treating a thymus cancer, comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
The present invention also provides a method of treating a thymus cancer, the method comprising administering to a subject diagnosed with a thymus cancer an
In some embodiments, the thymus cancer is a thymoma.
In some embodiments, the thymoma is a type a thymoma.
In some embodiments, the thymoma is an AB type thymoma.
In some embodiments, the thymoma is a B1 type thymoma.
In some embodiments, the thymoma is a B2 type thymoma.
In some embodiments, the thymoma is a B3 type thymoma.
In some embodiments, the thymus cancer is a malignant thymoma.
In some embodiments, the malignant thymoma is a low grade malignant thymoma.
In some embodiments, the malignant thymoma is a highly malignant thymoma.
In some embodiments, the thymus cancer is metastatic thymus cancer.
In some embodiments, the thymus cancer has metastasized to the lung, lymph nodes, heart, or bone.
In some embodiments, the subject has been treated with surgery, radiation therapy, chemotherapy, or hormone therapy.
In some embodiments, the subject has been treated with carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, ifosfamide, octreotide, paclitaxel, or pemetrexed, or any combination thereof.
Thymus cancers may be staged, for example, according to the American Society of Clinical Oncology (ASCO) staging system.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof comprises the heavy chain variable region (VH) of SEQ ID NO:7 and the light chain variable region (VL) of SEQ ID NO: 8.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is an IgG1, IgG2, and IgG3 or IgG4 isotype.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is an IgG4 isotype.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof is of the IgG4 isotype and comprises a proline at position 228 with residues numbered according to the EU index.
In some embodiments, the antagonistic anti-PD-1 antibody is nG4m (a) allotype.
In some embodiments, the antagonistic anti-PD-1 antibody or antigen binding fragment thereof has at least one substitution in the Fc region to modulate antibody effector function or antibody half-life.
In some embodiments, the antagonistic anti-PD-1 antibody comprises the heavy chain of
The present invention also provides a pharmaceutical composition comprising about 10mg/ml of an antagonistic anti-PD-1 antibody comprising the HC of SEQ ID NO:9 and the LC of SEQ ID NO:10, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate 20 and about 20 μ g/ml EDTA at pH 6.5.
SEQ ID NO:1
SYAIS
SEQ ID NO:2
GIIPIFDTANYAQKFQG
SEQ ID NO:3
PGLAAAYDTGSLDY
SEQ ID NO:4
RASQSVRSYLA
SEQ ID NO:5
DASNRAT
SEQ ID NO:6
QQRNYWPLT
SEQ ID NO:7
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARPGLAAAYDTGSLDYWGQGTLVTVSS
SEQ ID NO:8
EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNYWPLTFGQGTKVEIK
SEQ ID NO:9
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARPGLAAAYDTGSLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:10
EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNYWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
The present invention also provides a pharmaceutical composition comprising between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5; about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
In some embodiments, the lyophilized formulation comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA, at a pH of 6.5.
The invention also provides a pharmaceutical product comprising between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, at a pH of 6.5;
about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
In some embodiments, the lyophilized formulation comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA, at a pH of 6.5.
In some embodiments, the lyophilized formulation is reconstituted into sterile water for injection (sffi).
The invention also provides a pharmaceutical product comprising cetrellab in a volume of about 3.3ml, about 10mg/ml, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5.
The invention also provides a pharmaceutical product comprising a lyophilized formulation comprising about 90mg of cetrellab, which upon reconstitution to about 3.3ml comprises about 30mg/ml of cetrellab, about 10mM of histidine, about 8.0% (w/v) of sucrose, about 0.04% (w/v) of polysorbate-20 and about 20 μ g/ml of EDTA, at a pH of 6.5.
The invention also provides a pharmaceutical product comprising a lyophilized formulation comprising about 240mg of cetrellab, which upon reconstitution to about 8.6ml comprises about 30mg/ml of cetrellab, about 10mM of histidine, about 8.0% (w/v) of sucrose, about 0.04% (w/v) of polysorbate-20 and about 20 μ g/ml of EDTA, at a pH of 6.5.
The invention also provides a pharmaceutical product for the treatment of cancer comprising between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
In some embodiments, the lyophilized formulation comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA, at a pH of 6.5.
In some embodiments, a pharmaceutical product for treating lung cancer, non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, bladder cancer, gastrointestinal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, liver cancer, colorectal cancer (CRC), colon cancer, gallbladder cancer, biliary tract cancer, ovarian cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, endometrial cancer, Small Cell Lung Cancer (SCLC), breast cancer, pancreatic cancer, renal cell cancer, liver cancer, Merkel cell cancer, primary mediastinal B-cell lymphoma (PMBCL), hodgkin's lymphoma, non-hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBLC), multiple myeloma, glioblastoma, urothelial cancer, salivary gland cancer, mesothelioma, anal cancer, prostate cancer, basal cell carcinoma, and advanced skin squamous cell carcinoma (CSCC), or any combination thereof, is provided.
In some embodiments, a pharmaceutical product for treating NSCLC, melanoma, bladder cancer, renal cell carcinoma, SLCL, CRC, gastric cancer, prostate cancer, or esophageal cancer is provided.
In some embodiments, a pharmaceutical product for treating NSCLC with high PD-L1 is provided.
In some embodiments, a pharmaceutical product for treating MSI-H CRC or dMMR CRC is provided.
In some embodiments, a pharmaceutical product for treating non-uveal melanoma is provided.
In some embodiments, the pharmaceutical product
Administered at a dose of about 240mg once every two weeks;
administered once every four weeks at a dose of about 480 mg; or
An initial dose of about 240mg followed by a second dose of about 480mg six weeks after the initial dose, and then once every four weeks at a dose of about 480 mg; or
The initial dose was about 240mg, followed by a second dose of about 480mg six weeks after the initial dose, and then every two weeks at a dose of about 240 mg.
In some embodiments, the pharmaceutical product is administered by intravenous administration or by subcutaneous administration, or a combination thereof.
Generation of antibodies for use in the methods of the invention
Antagonistic anti-PD-1 antibodies or antigen-binding fragments thereof for use in the methods of the invention can be generated using a variety of techniques. For example, monoclonal antibodies can be generated using the hybridoma method described by Kohler and Milstein. In the hybridoma method, a mouse or other host animal (such as a hamster, rat, or monkey) is immunized with a human and/or cyno PD-1 antigen (such as the extracellular domain of PD-1), after which spleen cells from the immunized animal are fused with myeloma cells using standard methods to form hybridoma cells. Colonies arising from a single immortalized hybridoma cell can be screened for the production of antibodies having desired characteristics, such as binding specificity, cross-reactivity or lack thereof, affinity for the antigen, and function, such as antagonistic activity.
Exemplary humanization techniques that include selection of human acceptor frameworks include CDR grafting (U.S. Pat. No. 5,225,539), SDR grafting (U.S. Pat. No. 6,818,749), resurfacing (Padlan, (1991) Mol Immunol 28:489-499), specific residue-determining resurfacing (U.S. Pat. publication No. 2010/0261620), human framework remodeling (U.S. Pat. No. 8,748,356), or super-humanization (U.S. Pat. No. 7,709,226). In these methods, the CDRs or a subset of CDR residues of the parent antibody are transferred to a human framework, which can be selected based on their overall homology to the parent framework, based on similarity of CDR lengths or canonical structural identity, or a combination thereof.
The humanized antibody can be further optimized to improve its selectivity or affinity for the desired antigen by: by using techniques such as those described in international patent publications WO1090/007861 and WO1992/22653, modified framework support residues are introduced to maintain binding affinity (back-mutations), or by introducing variants at any CDR, for example, to improve the affinity of an antibody.
Transgenic animals, such as mice or rats, whose genomes carry the human immunoglobulin (Ig) loci can be used to produce antibodies against PD-1 and are described, for example, in U.S. Pat. No. 6,150,584, International patent publication WO1999/45962, International patent publication WO2002/066630, WO2002/43478, WO2002/043478, and WO 1990/04036. Endogenous immunoglobulin loci in such animals can be disrupted or deleted, and at least one human immunoglobulin locus, in whole or in part, can be inserted into the genome of the animal by homologous or nonhomologous recombination using transchromosomes or minigenes. Companies such as Regeneron (http:// _ ww _ Regeneron _ com), Harbour Antibodies (http:// _ ww _ hardwoods _ com), Open Monoclonal Technology, Inc. (OMT) (http:// _ ww _ omptinc _ net), KyMab (http:// _ ww _ KyMab _ com), Trianni (http:// _ www.trianni _ com), and Ablexis (http:// _ ww _ enablers _ com) may be invited to use the above techniques to provide human Antibodies against selected antigens.
The antibody may be selected from phage display libraries in which the phage are engineered to express human immunoglobulins or portions thereof, such as Fab, single chain antibody (scFv), or unpaired or paired antibody variable regions. Antibodies of the invention can be isolated, for example, using phage pIX coat protein from phage display libraries expressing the heavy and light chain variable regions of the antibody as fusion proteins, as described in Shi et al, (2010) J Mol Biol 397:385-96 and International patent publication WO 09/085462. The library can be screened for phage binding to human and/or cyno PD-1 and the positive clones obtained can be further characterized, Fab isolated from clone lysates and expressed as full-length IgG.
The CDRs of an antibody can be grafted onto any human framework and the resulting antibody can be tested for function. For example, antibody JNJ-63723283 comprises a framework derived from the human germline genes IGHV1-69 and IGKV 3-11. Alternatively, JNJ-63723283HCDR can be grafted to other IGHV1 germline cytokine panel frameworks and LCDR can be grafted to other IGKV3 germline cytokine panel frameworks and the resulting antibodies tested for desired function. Human germline gene sequences are well known and can be derived, for example, from ImmunoGeneTiCs Information
The preparation of the immunogenic antigen and the production of the monoclonal antibody can be carried out using any suitable technique, such as recombinant protein production. The immunogenic antigen may be administered to the animal in the form of a purified protein or protein mixture (including whole cells or cell extracts or tissue extracts), or the antigen may be formed de novo in the animal from a nucleic acid encoding the antigen or a portion thereof.
Method for producing antibody
Methods for large scale production of antibodies are known. The antibody can be produced, for example, in CHO cells cultured using known methods. As a first step in the purification process, the antibody may be isolated and/or purified from the culture medium by removing solids by centrifugation or filtration. The antibody may be further purified by standard methods including chromatography (e.g., ion exchange chromatography, affinity chromatography, size exclusion chromatography, and hydroxyapatite chromatography), gel filtration, centrifugation, or differential solubility, ethanol precipitation, or by any other available technique for purifying antibodies. Protease inhibitors such as phenylmethylsulfonyl fluoride (PMSF), leupeptin, pepstatin, or aprotinin may be added at any or all stages to reduce or eliminate degradation of the antibody during the purification process. One of ordinary skill in the art will appreciate that the exact purification technique will vary depending on the identity of the polypeptide or protein to be purified, the identity of the cell expressing the polypeptide or protein, and the composition of the medium in which the cell is grown.
Other embodiments of the invention
Certain other embodiments of the invention are set forth below in accordance with the disclosure elsewhere herein. The features of the embodiments of the invention set forth above as being relevant to the invention disclosed herein also relate to each of all of these other numbered embodiments.
1) An
2) The
3) The
a) Administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks at a dose of about 240 mg;
b) administered at a dose of about 240mg once every two weeks;
c) administered at a dose of about 240mg once every three weeks;
d) administered once every four weeks at a dose of about 240 mg;
e) administered once every five weeks at a dose of about 240 mg;
f) administered at a dose of about 240mg once every six weeks;
g) administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks at a dose of about 480 mg;
h) administered at a dose of about 480mg once every two weeks;
i) administered at a dose of about 480mg once every three weeks;
j) administered once every four weeks at a dose of about 480 mg;
k) administered once every five weeks at a dose of about 480 mg; or
l) is administered at a dose of about 480mg once every six weeks.
4) The
5) The
6) The
7) The
8) The
9) The
10) The
11) The
12) The
13) The
14) The
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18) The
a) Administering or providing for administration in the form of a pharmaceutical composition comprising about 10mg/ml to about 30mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5;
b) administering or providing for administration in the form of a pharmaceutical composition comprising about 10mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at a pH of 6.5;
c) administering or providing for administration in the form of a pharmaceutical composition comprising about 30mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20, and about 20 μ g/ml EDTA at a pH of 6.5;
d) providing for administration as a lyophilized formulation comprising between about 90mg and about 240mg of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients;
e) providing for administration as a lyophilized formulation comprising about 90mg of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients; or
f) Providing for administration as a lyophilized formulation comprising about 240mg of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients.
19) The
20) The
21) The
22) The
23) The
24) The
25) The
26) The
27) The
28) The
29) The
30) The
31) The
32) The
33) The
34) The
35) The
36) The
37) A pharmaceutical composition comprising
a) Between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
b) about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
c) about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
d) a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
e) a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
f) A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
38) The pharmaceutical composition according to
39) A pharmaceutical product comprising
a) Between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
b) about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
c) about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
d) a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
e) a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
f) A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
40) The pharmaceutical product according to embodiment 39, wherein the lyophilized formulation of d), e) and/or f) comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5.
41) A pharmaceutical product for treating a subject having cancer, the pharmaceutical product comprising
a) Between about 10mg/ml and about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5;
b) about 10mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
c) about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA, pH 6.5;
d) a lyophilized formulation comprising between about 90mg and about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients;
e) a lyophilized formulation comprising about 90mg of cetrilimab and one or more pharmaceutically acceptable excipients; or
f) A lyophilized formulation comprising about 240mg of cetrilimab and one or more pharmaceutically acceptable excipients.
42) The pharmaceutical product according to embodiment 41, wherein the lyophilized formulation of d), e) and/or f) comprises, after reconstitution, about 30mg/ml cetrellab, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% (w/v) polysorbate-20 and about 20 μ g/ml EDTA at pH 6.5.
43) The pharmaceutical product according to embodiment 41, wherein the cancer is lung cancer, non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, bladder cancer, gastrointestinal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, liver cancer, colorectal cancer (CRC), colon cancer, gallbladder cancer, biliary tract cancer, ovarian cancer, fallopian tube cancer, cervical cancer, peritoneal cancer, endometrial cancer, Small Cell Lung Cancer (SCLC), breast cancer, pancreatic cancer, renal cell cancer, liver cancer, Merkel cell cancer, primary mediastinal B-cell lymphoma (PMBCL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBLC), multiple myeloma, glioblastoma, urothelial cancer, salivary gland cancer, mesothelioma, anal cancer, prostate cancer, basal cell carcinoma, and advanced skin squamous cell carcinoma (CSCC), or any combination thereof.
44) The pharmaceutical product of embodiment 43, wherein
a) The NSCLC is a high PD-L1 NSCLC;
b) the CRC is MSI-H CRC or dMMR CRC; or
c) The melanoma is non-uveal melanoma; or any combination thereof.
45) The pharmaceutical product of embodiment 41, wherein the pharmaceutical product
a) Administered at a dose of about 240mg once every two weeks;
b) administered once every four weeks at a dose of about 480 mg; or
c) An initial dose of about 240mg followed by a second dose of about 480mg six weeks after the initial dose, and then once every four weeks at a dose of about 480 mg; or
d) The initial dose is about 240mg, followed by a second dose of about 480mg six weeks after the initial dose, and then every two weeks at a dose of about 240 mg.
46) The pharmaceutical product of embodiment 41, wherein the pharmaceutical product is administered by intravenous administration or by subcutaneous administration, or a combination thereof.
47) A method of treating cancer, comprising administering to a subject diagnosed with the cancer an
48) The method of embodiment 47, comprising providing an
49) The method of embodiment 48, wherein the cancer is an advanced solid tumor.
50) The method of any one of embodiments 47-49, wherein the subject has received or is unable to receive at least one prior therapeutic agent used to treat the cancer.
51) The method according to any one of embodiments 47-50, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 80mg, about 160mg, about 240mg, about 320mg, about 400mg, about 480mg, about 560mg, about 720mg, about 800mg, about 880mg, or about 960mg once every 2, 3, 4, 5, or 6 weeks.
52) The method according to any one of embodiments 47-51, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of about 240mg once every 2 weeks or at a dose of about 480mg once every 4 weeks.
53) The method according to any one of embodiments 47-52, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is provided in the form of a pharmaceutical composition comprising about 10mg/ml of the antagonist anti-PD-1 antibody or antigen-binding fragment thereof, about 10mM histidine, about 8.0% (w/v) sucrose, about 0.04% polysorbate-20 and about 20 μ g/ml EDTA at a pH of 6.5.
54) The method according to any one of embodiments 47-53, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is administered by intravenous infusion.
55) The method according to any one of embodiments 47-54, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is diluted to a volume of between about 100ml and 1000ml prior to administration.
56) The method according to any one of embodiments 47-55, wherein the duration of the intravenous infusion is between about 20 minutes and about 80 minutes.
57) The method according to any one of embodiments 47-56, wherein the duration of the intravenous infusion is about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, or about 80 minutes.
58) The method of any one of embodiments 47-57, wherein the cancer is selected from thymus cancer, non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC), melanoma, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, and colorectal cancer (CRC).
59) The method of any one of embodiments 47-58, wherein the thymus cancer is a thymoma, a malignant thymoma, or a metastatic thymus cancer, or any combination thereof.
60) The method of any one of embodiments 47-59, wherein the thymoma is a type A thymoma, an AB type thymoma, a type B1 thymoma, a type B2 thymoma, or a type B3 thymoma.
61) The method of any one of embodiments 47-60, wherein the malignant thymoma is a low grade thymoma or a high grade thymoma.
62) The method of any one of embodiments 47-61, wherein the thymus cancer has metastasized to the lung, lymph nodes, heart, or bone.
63) The method of any one of embodiments 47-62, wherein the subject has been treated with surgery, radiation therapy, chemotherapy, or hormone therapy.
64) The method of any one of embodiments 47-63, wherein the chemotherapy is carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, ifosfamide, octreotide, paclitaxel, or pemetrexed, or any combination thereof.
65) The method of any one of embodiments 47-64, wherein the CRC is a high microsatellite instability (MSI-H) CRC or a mismatch repair deficiency (dMMR) CRC, or a combination thereof.
66) The method of any one of embodiments 47-65, wherein the CRC is a stage II CRC or a stage III CRC.
67) The method of any one of embodiments 47-66, wherein the subject is refractory to treatment with fluoropyrimidine, oxaliplatin or irinotecan, or has recurrent CRC after treatment with fluoropyrimidine, oxaliplatin or irinotecan, or any combination thereof.
68) The method of any one of embodiments 47-67, wherein the subject has not received PD-1 axis therapy.
69) The method of any one of embodiments 47-68, wherein the subject has not received PD-1 axis therapy and has received at least one prior therapeutic agent used to treat the cancer.
70) The method of any one of embodiments 47-69, wherein the cancer is PD-L1 positive.
71) The method of any one of embodiments 47-70, wherein the cancer is high PD-L1.
72) The method of any one of embodiments 47-71, wherein said method achieves an Overall Response Rate (ORR) of at least 15% in a group of subjects diagnosed with said cancer.
73) The method of any one of embodiments 47-72, wherein the method achieves an ORR of at least about 35% in a group of subjects diagnosed with MSI-HCRC, at least about 35% in a group of subjects diagnosed with dMMR CRC, at least about 30% in a group of subjects diagnosed with NSCLC with high PD-L1, or at least about 25% in a group of subjects diagnosed with melanoma, or any combination thereof.
74) The method of any one of embodiments 47-73, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain variable region (VH) of SEQ ID NO:7 and the light chain variable region (VL) of SEQ ID NO: 8.
75) The method of any one of embodiments 47-74, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof is an IgG1, IgG2, and IgG3 or IgG4 isotype.
76) The method of any one of embodiments 47-75, wherein the antagonist anti-PD-1 antibody comprises a heavy chain of
77) A pharmaceutical composition comprising about 10mg/ml of an antagonistic anti-PD-1 antibody comprising the Heavy Chain (HC) of
78) A method of treating a thymus cancer, comprising administering to a subject diagnosed with said thymus cancer an
79) The method of any embodiment 78, wherein the thymus cancer is a thymoma, a malignant thymoma, or a metastatic thymus cancer, or any combination thereof.
80) The method of any embodiment 78 or 79, wherein the thymoma is a type A thymoma, an AB type thymoma, a type B1 thymoma, a type B2 thymoma, or a type B3 thymoma.
81) The method of any one of embodiments 78-80, wherein the malignant thymoma is a low grade thymoma or a high grade thymoma.
82) The method of any one of embodiments 78-81, wherein the thymus cancer has metastasized to the lung, lymph nodes, heart, or bone.
83) The method according to any one of embodiments 78-82, wherein said subject has been or will be treated with surgery, radiation therapy, chemotherapy or hormone therapy, or any combination thereof.
84) The method according to any one of embodiments 78-83, wherein the chemotherapy is carboplatin, cisplatin, cyclophosphamide, doxorubicin, etoposide, ifosfamide, octreotide, paclitaxel, or pemetrexed, or any combination thereof.
85) The method of any one of embodiments 78-84, wherein the subject has not received PD-1 axis therapy, has received and/or is unable to receive at least one prior therapeutic agent used to treat the cancer, or any combination thereof.
86) The method according to any one of embodiments 78-85, wherein the subject has not received PD-1 axis therapy and has received at least one prior therapeutic agent used to treat the cancer.
87) The method of any one of embodiments 78-86, wherein the cancer is PD-L1 positive.
88) The method of any one of embodiments 78-87, wherein the cancer is high PD-L1.
89) The method according to any one of embodiments 78-88, wherein said method achieves an Overall Response Rate (ORR) of at least 15% in a group of subjects diagnosed with said cancer.
90) The method according to any one of embodiments 78-89, wherein the antagonist anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain variable region (VH) of SEQ ID NO:7 and the light chain variable region (VL) of SEQ ID NO: 8.
91) The method of any one of embodiments 78-90, wherein the antagonist anti-PD-1 antibody is an IgG1, IgG2 and IgG3 or IgG4 isotype.
92) The method according to any one of embodiments 78-91, wherein the antagonist anti-PD-1 antibody comprises a heavy chain of
93) The method according to any one of embodiments 78-92, wherein the
The invention will now be described with reference to the following specific, non-limiting examples.
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