Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof

Abstract

The present disclosure provides isolated monoclonal antibodies that specifically bind to LAG-3 with high affinity, particularly human monoclonal antibodies. Preferably, the antibodies bind human LAG-3. In certain embodiments, the antibodies bind both human and monkey LAG-3 but do not bind mouse LAG-3. The invention provides anti-LAG-3 antibodies that can inhibit the binding of LAG-3 to MHC Class II molecules and that can stimulate antigen- specific T cell responses. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention are also provided. This disclosure also provides methods for detecting LAG-3, as well as methods for treating stimulating immune responses using an anti-LAG-3 antibody of the invention. Combination therapy, in which an anti- LAG-3 antibody is co-administered with at least one additional immuno stimulatory antibody, is also provided.

1 . An isolated human monoclonal antibody, or an antigen-binding portion thereof, wherein the antibody binds human LAG-3 and exhibits at least two of the following properties:
 (a) binds monkey LAG-3;   (b) does not bind mouse LAG-3;   (c) inhibits binding of LAG-3 to major histocompatibility (MHC) class II molecules; and   (d) stimulates an immune response.   
     
     
         2 - 4 . (canceled) 
     
     
         5 . The antibody of  claim 1 , wherein the antibody stimulates interleukin-2 (IL-2) production in an antigen-specific T cell response. 
     
     
         6 . The antibody of  claim 1 , wherein the antibody stimulates an anti-tumor immune response. 
     
     
         7 . The antibody of  claim 1 , wherein the antibody binds an epitope of human LAG-3 comprising the amino acid sequence PGHPLAPG (SEQ ID NO: 76). 
     
     
         8 . The antibody of  claim 1 , wherein the antibody binds an epitope of human LAG-3 comprising the amino acid sequence (SEQ ID NO: 77) or PAAPSSWG (SEQ ID NO: 78). 
     
     
         9 . The antibody of  claim 1 , wherein said antibody binds to human LAG-3 with a K D  of 1×10 −7  M or less. 
     
     
         10 - 12 . (canceled) 
     
     
         13 . An isolated human monoclonal antibody, or antigen binding portion thereof, wherein the antibody cross-competes for binding to human LAG-3 with a reference antibody, wherein the reference antibody comprises:
 (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:   37 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 43;   (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:   38 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 44;   (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:   40 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 46;   (d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 45;   (e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 41 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:  47; or      (f) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 42 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 48.   
     
     
         14 - 22 . (canceled) 
     
     
         23 . The antibody of  claim 1 , which comprises:
 (i) (a) a heavy chain variable region CDR1 comprising SEQ ID NO: 1;
 (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 7; 
 (c) a heavy chain variable region CDR3 comprising SEQ ID NO: 13; 
 (d) a light chain variable region CDR1 comprising SEQ ID NO: 19; 
 (e) a light chain variable region CDR2 comprising SEQ ID NO: 25; and 
 (f) a light chain variable region CDR3 comprising SEQ ID NO:  31; or    
   (ii) (a) a heavy chain variable region CDR1 comprising SEQ ID NO: 2;
 (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 8; 
 (c) a heavy chain variable region CDR3 comprising SEQ ID NO: 14; 
 (d) a light chain variable region CDR1 comprising SEQ ID NO: 20; 
 (e) a light chain variable region CDR2 comprising SEQ ID NO: 26; and 
 (f) a light chain variable region CDR3 comprising SEQ ID NO: 32; or 
   (iii)(a) a heavy chain variable region CDR1 comprising SEQ ID NO: 4;
 (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 10; 
 (c) a heavy chain variable region CDR3 comprising SEQ ID NO: 16; 
 (d) a light chain variable region CDR1 comprising SEQ ID NO: 22; 
 (e) a light chain variable region CDR2 comprising SEQ ID NO: 28; and 
 (f) a light chain variable region CDR3 comprising SEQ ID NO: 34; or 
   (iv)(a) a heavy chain variable region CDR1 comprising SEQ ID NO: 3;
 (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 9; 
 (c) a heavy chain variable region CDR3 comprising GGY; 
 (d) a light chain variable region CDR1 comprising SEQ ID NO: 21; 
 (e) a light chain variable region CDR2 comprising SEQ ID NO: 27; and 
 (f) a light chain variable region CDR3 comprising SEQ ID NO: 33; or 
   (v) (a) a heavy chain variable region CDR1 comprising SEQ ID NO: 5;
 (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 11; 
 (c) a heavy chain variable region CDR3 comprising SEQ ID NO: 17; 
 (d) a light chain variable region CDR1 comprising SEQ ID NO: 23; 
 (e) a light chain variable region CDR2 comprising SEQ ID NO: 29; and 
 (f) a light chain variable region CDR3 comprising SEQ ID NO: 35; or 
   (vi)(a) a heavy chain variable region CDR1 comprising SEQ ID NO: 6;
 (b) a heavy chain variable region CDR2 comprising SEQ ID NO: 12; 
 (c) a heavy chain variable region CDR3 comprising SEQ ID NO: 18; 
 (d) a light chain variable region CDR1 comprising SEQ ID NO: 24; 
 (e) a light chain variable region CDR2 comprising SEQ ID NO: 30; and 
 (f) a light chain variable region CDR3 comprising SEQ ID NO: 36. 
   
     
     
         24 - 28 . (canceled) 
     
     
         29 . An isolated monoclonal antibody, or antigen binding portion thereof, comprising:
 (a) a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 37-42; and   (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 43-48;   
       wherein the antibody specifically binds a human LAG-3 protein. 
     
     
         30 - 35 . (canceled) 
     
     
         36 . A composition comprising the antibody, or antigen-binding portion thereof, of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         37 . An immunoconjugate comprising the antibody, or antigen-binding portion thereof, of  claim 1 , linked to a therapeutic agent. 
     
     
         38 - 42 . (canceled) 
     
     
         43 . An isolated nucleic acid molecule encoding the antibody, or antigen-binding portion thereof, of  claim 1 . 
     
     
         44 . An expression vector comprising the nucleic acid molecule of  claim 43 . 
     
     
         45 . A host cell comprising the expression vector of  claim 44 . 
     
     
         46 . A method for preparing an anti-LAG-3 antibody which comprises expressing the antibody in the host cell of  claim 45  and isolating the antibody from the host cell. 
     
     
         47 . A method of stimulating an antigen-specific T cell response comprising contacting said T cell with the antibody of  claim 1  such that an antigen-specific T cell response is stimulated. 
     
     
         48 . (canceled) 
     
     
         49 . A method of stimulating an immune response in a subject comprising administering the antibody of  claim 1  to the subject such that an immune response in the subject is stimulated. 
     
     
         50 - 51 . (canceled) 
     
     
         52 . A method for inhibiting growth of tumor cells in a subject comprising administering to the subject the antibody of  claim 1  such that growth of the tumor is inhibited in the subject. 
     
     
         53 . A method for treating viral infection in a subject comprising administering to the subject the antibody of  claim 1  such that the viral infection is treated in the subject. 
     
     
         54 . A method of stimulating an immune response in a subject comprising administering to the subject an the antibody of  claim 1  anti LAG 3 antibody and at least one additional immunostimulatory antibody such that an immune response in the subject is stimulated. 
     
     
         55 - 62 . (canceled)