Klrg1 signaling therapy

Abstract

A method of treating a subject can include administering to a subject in need thereof an effective amount of a killer cell lectin-like receptor G1 (KLRG1)/ligand binding agent, thereby disrupting KLRG1 signaling and activating CD8 + cytotoxic T and/or NK cells. A method of treating cancer can include administering to a subject in need thereof an effective amount of a killer cell lectin-like receptor G1 (KLRG1)/ligand binding agent. The methods can treat various cancers, for example melanoma, lung cancer, pancreatic cancer, glioma, breast cancer, ovarian cancer, metastatic breast cancer, and colon cancer.

1 . A method of treating metastatic breast cancer comprising administering to a subject in need thereof an effective amount of an antibody or a fragment thereof that binds human killer cell lectin-like receptor G1 (KLRG1), or by administering an antibody or fragment thereof that disrupts KLRG1 signaling and activates CD8+ cytotoxic T and/or NK cells by binding an extracellular domain of a human protein selected from the group: KLRG1, E-cadherin, N-cadherin, and R-cadherin, whereby said administration inhibits metastases, thereby treating said metastatic breast cancer. 
     
     
         2 . The method of  claim 1 , wherein said metastases inhibited by said treatment comprises inhibiting lung metastases. 
     
     
         3 . The method of  claim 2 , wherein said inhibition of lung metastases is evidenced by a reduction in the number of detectable lung nodules, and/or a reduction of lung weight. 
     
     
         4 . The method of  claim 3 , wherein said treatment provides a reduction in the number of detectable lung nodules by about 25%, about 30%, or preferably by about 50% (+/−5%, 10%), and/or said lung weight is reduced by at least 25%, preferably by about 50% (+/−5-10%). 
     
     
         5 . A method of treating metastatic breast cancer comprising administering to a subject in need thereof:
 (a) an effective amount of an antibody or a fragment thereof that binds human killer cell lectin-like receptor G1 (KLRG1), or by administering an antibody or fragment thereof that disrupts KLRG1 signaling and activates CD8+ cytotoxic T and/or NK cells by binding an extracellular domain of a human protein selected from the group: KLRG1, E-cadherin, N-cadherin, and R-cadherin; and   (b) an effective amount of an antibody or fragment thereof that binds PD-1,   whereby said administration inhibits metastases, thereby treating said metastatic breast cancer.   
     
     
         6 . The method of  claim 5 , wherein said metastases inhibited by said treatment comprises inhibiting lung metastases. 
     
     
         7 . The method of  claim 6 , wherein said treatment provides for a reduction of lung tumor volume and/or extended time of survival. 
     
     
         8 . The method of  claim 7 , wherein said lung tumor volume is reduced by about 25%. 
     
     
         9 . A method of treating colon cancer. comprising administering to a subject in need thereof:
 (a) an effective amount of an antibody or a fragment thereof that binds human killer cell lectin-like receptor G1 (KLRG1), or by administering an antibody or fragment thereof that disrupts KLRG1 signaling and activates CD8+ cytotoxic T and/or NK cells by binding an extracellular domain of a human protein selected from the group: KLRG1, E-cadherin, N-cadherin, and R-cadherin; and   (b) an effective amount of an antibody or fragment thereof that binds PD-1,   whereby said administration inhibits said colon cancer to a greater extent than said anti-KLRG1 antibody alone, thereby treating said colon cancer.   
     
     
         10 . A method of treating melanoma comprising administering to a subject in need thereof:
 (a) an effective amount of an antibody or a fragment thereof that binds human killer cell lectin-like receptor G1 (KLRG1), or by administering an antibody or fragment thereof that disrupts KLRG1 signaling and activates CD8+ cytotoxic T and/or NK cells by binding an extracellular domain of a human protein selected from the group: KLRG1, E-cadherin, N-cadherin, and R-cadherin, and   (b) an effective amount of an antibody or fragment thereof that binds PD-1,   whereby said administration inhibits said melanoma to a greater extent than said anti-KLRG1 antibody alone, thereby treating said melanoma.   
     
     
         11 . The method of any one of  claims 1 ,  5 ,  9 , and  10 , wherein the anti-KLRG1 antibody comprises a human or humanized antibody. 
     
     
         12 . The method of any one of  claims 1 ,  5 ,  9  and  10 , wherein the anti-KLRG1 antibody and the anti-PD-1 antibody are administered to the subject essentially simultaneously or at different time points. 
     
     
         13 . A combination therapy for treating colon cancer in a subject,
 wherein the combination therapy comprises administration of effective amounts of an anti-KLRG1 antibody and a checkpoint inhibitor,   wherein the checkpoint inhibitor comprises an anti-PD-1 antibody or antibody fragment, and   wherein the cancer is colon cancer.   
     
     
         14 . A combination therapy for treating colon cancer in a subject,
 wherein the combination therapy comprises administration of effective amounts of killer cell lectin-like receptor G1 (KLRG1)/ligand binding agent and a checkpoint inhibitor, and   wherein the checkpoint inhibitor is an anti-PD-1 antibody or antibody fragment.   
     
     
         15 . A combination therapy for treating melanoma in a subject,
 wherein the combination therapy comprises administration of effective amounts of an anti-KLRG1 antibody and a checkpoint inhibitor,   wherein the checkpoint inhibitor comprises an anti-PD-1 antibody or antibody fragment, and   wherein the cancer is melanoma.   
     
     
         16 . A combination therapy for treating melanoma in a subject,
 wherein the combination therapy comprises administration of effective amounts of killer cell lectin-like receptor G1 (KLRG1)/ligand binding agent and a checkpoint inhibitor, and   wherein the checkpoint inhibitor is an anti-PD-1 antibody or antibody fragment.   
     
     
         17 . The combination therapy of any one of  claims 13 - 16 , wherein the anti-PD-1 antibody inhibits, reduces, modulates, or abolishes signal transduction mediated by PD-1. 
     
     
         18 . The combination therapy of any one of  claims 13 - 16 , wherein the anti-KLRG1 antibody disrupts KLRG1 signaling, thereby activating CD8+ cytotoxic T cells and/or NK cells. 
     
     
         19 . The combination therapy of any one of  claims 13 - 16 , wherein the anti-KLRG1 antibody and the anti-PD-1 antibody are synergistic. 
     
     
         20 . The combination therapy of any one of  claims 13 - 16 , wherein the anti-KLRG1 antibody comprises a human or humanized antibody. 
     
     
         21 . The combination therapy of any one of  claims 13 - 16 , wherein the anti-KLRG1 antibody and the anti-PD-1 antibody are administered to the subject essentially simultaneously or at different time points.