Combination therapies targeting pd-1, tim-3, and lag-3

Abstract

This invention relates to combination therapies targeting two or all of PD-1, TIM-3, and LAG-3 using antibodies specific for these targets in patients who are in need of enhanced immunity. Also included in the invention are compositions useful in the therapies. The therapies are useful in treating diseases such as cancers.

What is claimed is: 
     
         1 . A composition comprising
 a) an anti-LAG-3 antibody or an antigen-binding portion thereof; and   b) an anti-PD-1 antibody or an antigen-binding portion thereof and/or an anti-TIM-3 antibody or an antigen-binding portion thereof;   wherein the anti-LAG-3 antibody or the antigen-binding portion thereof comprises H-CDR1-3 and L-CDR1-3 that comprise the amino acid sequences of SEQ ID NOs: 318-323, respectively.   
     
     
         2 . The composition of  claim 1 , wherein the anti-LAG-3 antibody or the antigen-binding portion thereof has at least one of the following properties:
 a) at a concentration of 20 μg/mL, reduces the binding of human LAG-3 to human MHC class II on A375 cells by greater than 85% compared to a negative control antibody as determined by a flow cytometric competition assay;   b) at a concentration of 20 μg/mL, reduces the binding of human LAG-3 to human MHC class II on A375 cells to between 35% and 85% compared to a negative control antibody as determined by a flow cytometric competition assay;   c) blocks binding between human LAG-3 expressed on Jurkat cells and human MHC class II expressed on Raji cells;   d) binds to human LAG-3 with an EC50 of 0.1 nM or less as measured by flow cytometry;   e) binds to cynomolgus LAG-3 with an EC50 of 0.3 nM or less as measured by flow cytometry;   f) binds to human LAG-3 with a K D  of 3.0×10 −8  M or less as measured by surface plasmon resonance;   g) binds to cynomolgus LAG-3 with a K D  of 1.5×10 −7  M or less as measured by surface plasmon resonance;   h) binds to mouse LAG-3 with a K D  of 3.5×10 −8  M or less as measured by surface plasmon resonance;   i) stimulates IL-2 production in Staphylococcal enterotoxin B (SEB) treated human peripheral blood mononuclear cells (PBMCs);   j) reduces cellular levels of LAG-3 in human T cells;   k) reduces soluble levels of LAG-3 in the culture of human T cells;   l) induces tumor growth regression in vivo;   m) delays tumor growth in vivo; and   n) does not bind to the same epitope of human LAG-3 as antibody 25F7-Lag3.5.   
     
     
         3 . The composition of  claim 1 , wherein the anti-LAG-3 antibody or the antigen-binding portion thereof comprises a heavy chain variable domain and a light chain variable domain that comprise the amino acid sequences of SEQ ID NOs: 316 and 317, respectively. 
     
     
         4 . A composition comprising
 a) an anti-LAG-3 antibody; and   b) an anti-PD-1 antibody or an antigen-binding portion thereof and/or an anti-TIM-3 antibody or an antigen-binding portion thereof;   wherein the anti-LAG-3 antibody comprises a heavy chain that comprises the amino acid sequences of SEQ ID NO: 316 and 375 and a light chain that comprises the amino acid sequences of SEQ ID NOs: 317 and 378.   
     
     
         5 . A pharmaceutical composition comprising:
 a) the composition of  claim 1 ; and   b) a pharmaceutically acceptable excipient.   
     
     
         6 . A pharmaceutical composition comprising:
 a) the composition of  claim 4 ; and   b) a pharmaceutically acceptable excipient.   
     
     
         7 . A method of enhancing immunity in a human patient in need thereof, comprising administering to the patient
 a) an anti-LAG-3 antibody or an antigen-binding portion thereof; and   b) an anti-PD-1 antibody or an antigen-binding portion thereof and/or an anti-TIM-3 antibody or an antigen-binding portion thereof;   wherein the anti-LAG-3 antibody or the antigen-binding portion thereof comprises H-CDR1-3 and L-CDR1-3 that comprise the amino acid sequences of SEQ ID NOs: 318-323, respectively.   
     
     
         8 . The method of  claim 7 , wherein the anti-LAG-3 antibody or the antigen-binding portion thereof comprises a heavy chain variable domain and a light chain variable domain that comprise the amino acid sequences of SEQ ID NOs: 316 and 317, respectively. 
     
     
         9 . The method of  claim 7 , wherein the anti-LAG-3 antibody comprises a heavy chain that comprises the amino acid sequences of SEQ ID NO: 316 and 375 and a light chain that comprises the amino acid sequences of SEQ ID NOs: 317 and 378. 
     
     
         10 . The method of  claim 7 , wherein the patient has cancer. 
     
     
         11 . The method of  claim 10 , wherein the cancer is a hematological malignancy or solid tumor. 
     
     
         12 . The method of  claim 10 , wherein the cancer is leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myeloma. 
     
     
         13 . The method of  claim 10 , wherein the cancer is melanoma, non-small cell lung cancer, bladder cancer, head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma, Merkel-cell carcinoma, fibrosarcoma, gliosarcoma, or glioblastoma. 
     
     
         14 . The method of  claim 7 , further comprising administering to the patient radiation therapy, or at least one of a chemotherapeutic agent, an anti-neoplastic agent, and an anti-angiogenic agent. 
     
     
         15 . The method of  claim 7 , wherein the antibodies or antigen-binding portions thereof are administered in a single pharmaceutical composition. 
     
     
         16 . The method of  claim 7 , wherein the antibodies or antigen-binding portions thereof are administered in separate pharmaceutical compositions.