Combination of Anti-LAG-3 Antibodies and Anti-PD-1 Antibodies to Treat Tumors

Abstract

Provided are methods for clinical treatment of tumors (e.g., advanced solid tumors) using an anti-LAG-3 antibody in combination with an anti-PD-1 antibody.

What is claimed is: 
     
         1 . A method of treating a solid tumor in a human patient, the method comprising administering to the patient an effective. amount of each of:
 (a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID N0:3, and CDR 1 1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:5,   (b) an anti-PD-1antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:1.9, and CDR I, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:21,   wherein the method comprises at least one administration cycle, wherein the cycle is a period of eight weeks, wherein for each of the at least one cycles, four doses of the anti-LAG-3 antibody are administered at a dose of 3, 20, 80, or 240 mg and four doses of the anti-PD-1 antibody are administered at a dose of 80 or 240 mg.   
     
     
         2 . The method of claim I, wherein the anti-LAG-3 antibody and anti-PD-1 antibody are administered at the following doses:
 (a) 3 mg anti-LAG-3 antibody and 80 mg of anti-PD-1 antibody;   (b) 3 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody;   (c) 20 nig anti--LAG-3 antibody and 240 mg of anti-PD-1 antibody;   (d) 80 mg anti.-LAG-3 antibody and 240 mg of anti-PD-1 antibody; or   (e) 240 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody.   
     
     
         3 . The method of  claim 1 , wherein the anti-PD-1 and anti.-LAG-3 antibodies are formulated for intravenous administration. 
     
     
         4 . The method of  claim 1 , wherein the anti-PD-1 and anti-LAG-3 antibodies are formulated together. 
     
     
         5 . The method of  claim 1 , wherein the anti-PD-1 and anti-LAG-3 antibodies are formulated separately. 
     
     
         6 . The method of  claim 1 , wherein the treatment consists of up to 12 cycles. 
     
     
         7 . The method of  claim 1 , wherein anti-PD-1 antibody is administered on Days 1, 15, 29, and 43 of each cycle. 
     
     
         8 . The method of  claim 1 , wherein anti-LAG-3 antibody is administered on Days 1, 15, 29, and 43 of each cycle. 
     
     
         9 . The method of  claim 1 , wherein the anti-PD-1 antibody is administered prior to administration of the anti-LAG-3 antibody. 
     
     
         10 . The method of  claim 9 , wherein the anti-LAG-3 antibody is administered within about 30 minutes prior to administration of the anti-PD-1 antibody. 
     
     
         11 . The method of  claim 1 , wherein the anti-PD-1 antibody is administered after administration of the anti-LAG-3 antibody. 
     
     
         12 . The method of  claim 1 , wherein the anti-PD-1 antibody is administered concurrently with the anti-LAG-3 antibody. 
     
     
         13 . The method of  claim 1 , wherein the treatment produces at least one therapeutic effect chosen from a reduction in size of a tumor, reduction in number of metastasic lesions over time, complete response, partial response, and stable disease. 
     
     
         14 . The method of  claim 1 , wherein the solid tumor is chosen from melanoma, non-small cell lung cancer (NSCLC), human papilloma virus (HPV)-related tumor, and gastric adenocarcinoma. 
     
     
         15 . The Method of  claim 1 , wherein the anti-LAG-3 antibody comprises
 (a) a heavy chain variable region CDR1 comprising the sequence set forth SEQ ID NO:7;   (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:8;   (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:9:   (d) a light chain variable region CDR1 comprising the sequence set forth in SEQ ID NO:10;   (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ NO:I 1; and   (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:12.   
     
     
         16 . The method of  claim 1 , wherein the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ ID NOs:3 and 5, respectively. 
     
     
         17 . The method of  claim 1 , wherein the anti-LAG-3 antibody comprises heavy and light chains comprising the sequences set forth in SEQ ID NOs:1 and 2, respectively. 
     
     
         18 . The method of  claim 1 , wherein the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 comprising the sequence set forth in SEQ NO:23;
 (b) a heavy chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:24;   (c) a heavy chain variable region CDR3 comprising the sequence set forth in SEQ ID NO:25;   (d) a light chain variable region CDR1 comprising the sequence set forth SEQ ID NO:26;   (e) a light chain variable region CDR2 comprising the sequence set forth in SEQ ID NO:27; and   (f) a light chain variable region CDR3 comprising the sequence set forth in SEQ NO:28.   
     
     
         19 . The method of  claim 1 , wherein the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the sequences set forth in SEQ 1D NOs:19 and 21, respectively. 
     
     
         20 . The method of  claim 1 , wherein the anti-PD-1 antibody comprises heavy and light chains comprising the sequences as set forth in SEQ ID NOs:17 and 18, respectively. 
     
     
         21 . A kit for treating a solid tumor in a human patient, the kit comprising:
 (a) a dose of an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:5;   (b) a dose of an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:19, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ IL) NO:21; and   (c) instructions for using the anti-LAG-3 antibody and anti-PD-1 antibody in the method of  claim 1 .   
     
     
         22 . An anti-LAG-3 antibody comprising CDRI, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2 and CRS domains of the light chain variable region having the sequence set forth in SEQ ID NO:5, for co-administration with an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:19, and CDRI, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:21, in at least one cycle, wherein for each cycle four doses of the anti-LAG-3 antibody are administered at a dose of 3, 20, 80, or 240 mg and four doses of the anti-PD-1 antibody are administered at a dose of 80 or 240 mg. 
     
     
         23 . An anti-LAG-3 antibody comprising CDR1, CDR2. and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:3, and CDRI, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:5, for co-administration with an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO:19, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:21 in at least one cycle, wherein for each cycle four doses of the anti-LAG-3 antibody are administered at a dose of 3, 20, 80, or 240 mg/kg and four doses of the anti-PD-1 antibody are administered at a dose of 80 of 240 mg/kg.