JPWO2020055702A5 - - Google Patents

Claims (27)

A method of treating non-microsatellite high instability (non-MSI-H) or good mismatch repair (pMMR) colorectal cancer in an individual for use in combination therapy comprising administering a PD-1 antagonist and a LAG3 antagonist to the individual A pharmaceutical composition for the treatment of
wherein said pharmaceutical composition comprises either a PD-1 antagonist or a LAG3 antagonist. 2. The pharmaceutical composition of claim 1, wherein the PD-1 antagonist is a monoclonal antibody or antigen-binding fragment thereof. wherein the individual is human and the PD-1 antagonist is a monoclonal antibody or antigen-binding fragment thereof that specifically binds to human PD-1 and blocks binding of human PD-L1 to human PD-1. Item 1. The pharmaceutical composition of Item 1. 4. The pharmaceutical composition of claim 3, wherein the PD-1 antagonist also blocks binding of human PD-L2 to human PD-1. The PD-1 antagonist is an antibody or antigen-binding fragment thereof comprising (a) the light chain CDRs of SEQ ID NOs: 1, 2 and 3 and (b) the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8. 5. The pharmaceutical composition of claim 4. The PD-1 antagonist is an anti-PD-1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:9 and the light chain comprises a light chain comprising SEQ ID NO:4. 5. The pharmaceutical composition of Claim 4, comprising a chain variable region. 5. The pharmaceutical composition of claim 4, wherein the PD-1 antagonist is an anti-PD-1 antibody comprising heavy and light chains, wherein the heavy chain comprises SEQ ID NO:10 and the light chain comprises SEQ ID NO:5. thing. 5. The pharmaceutical composition of claim 4, wherein the PD-1 antagonist is pembrolizumab. 5. The pharmaceutical composition of claim 4, wherein the PD-1 antagonist is a pembrolizumab variant. 5. The pharmaceutical composition of claim 4, wherein the PD-1 antagonist is nivolumab. 11. The pharmaceutical composition of any one of claims 1-10, wherein the LAG3 antagonist is a monoclonal antibody or antigen-binding fragment thereof that blocks binding of LAG3 to MHC class II molecules. 3. The claim wherein the LAG3 antagonist is an antibody or antigen-binding fragment thereof comprising (a) the light chain CDRs of SEQ ID NOs:26, 27 and 28 and (b) the heavy chain CDRs of SEQ ID NOs:29, 30 and 31. The pharmaceutical composition of any one of 1-10. The LAG3 antagonist is an anti-LAG3 monoclonal antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises a light chain variable region comprising SEQ ID NO:24 11. The pharmaceutical composition of any one of claims 1-10, comprising 11. Any one of claims 1-10, wherein the LAG3 antagonist is an anti-LAG3 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO:22 pharmaceutical composition of 11. The pharmaceutical composition of any one of claims 1-10, wherein the LAG3 antagonist is an Ab6 variant. 11. The pharmaceutical composition of any one of claims 1-10, wherein the LAG3 antagonist is relatrimab. the PD-1 antagonist is a humanized anti-PD-1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs: 6, 7 and 8; and the light chain comprises a light chain variable region comprising the light chain CDRs of SEQ ID NOS: 1, 2 and 3;
and the LAG3 antagonist is a humanized anti-LAG3 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOS:29, 30 and 31, and a light 2. The pharmaceutical composition of Claim 1, wherein the chain comprises a light chain variable region comprising the light chain CDRs of SEQ ID NOs:26, 27 and 28. The PD-1 antagonist is an anti-PD-1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:9 and the light chain comprises a light chain comprising SEQ ID NO:4. comprising a chain variable region;
and the LAG3 antagonist is an anti-LAG3 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region comprising SEQ ID NO:25 and the light chain comprises a light chain variable region comprising SEQ ID NO:24 2. The pharmaceutical composition of Claim 1, comprising a region. the PD-1 antagonist is an anti-PD-1 antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO:10 and the light chain comprises SEQ ID NO:5;
and the pharmaceutical composition of claim 1, wherein the LAG3 antagonist is an anti-LAG3 antibody comprising heavy and light chains, wherein the heavy chain comprises SEQ ID NO:23 and the light chain comprises SEQ ID NO:22. 20. The pharmaceutical composition of any one of claims 1-19, wherein the PD-1 antagonist and the LAG3 antagonist are co-formulated. 20. The pharmaceutical composition of any one of claims 1-19, wherein the PD-1 antagonist and the LAG3 antagonist are co-administered. 22. Any of claims 1-21, wherein the individual has not been previously treated with anti-PD-1 or anti-PD-L1 therapy, or has been confirmed as progressive upon prior anti-PD-1 therapy. or the pharmaceutical composition of claim 1. 23. The pharmaceutical composition of any one of claims 1-22, wherein the individual's tumor cells are positive for PD-L1 expression. 23. The pharmaceutical composition of any one of claims 1-22, wherein the individual has a mononuclear inflammation density score ≧2 for PD-L1 expression. 23. The pharmaceutical composition of any one of claims 1-22, wherein the individual has a combined positive score ≧1% for PD-L1 expression. 26. The pharmaceutical composition of claim 24 or 25, wherein PD-L1 expression is measured by the PD-L1 IHC 22C3 pharmDx assay. 27. The pharmaceutical composition of any one of claims 1-26, further comprising administering mFOLFOX7 (oxaliplatin, leucovorin and 5-FU) or FOLFIRI (irinotecan, leucovorin and 5-FU).