Antibodies against PD-1 and uses therefor

Abstract

This disclosure provides antibodies and antigen-binding fragments that can act as agonists and/or antagonists of PD-1 (Programmed Death 1), thereby modulating immune responses in general, and those mediated by TcR and CD28, in particular. The disclosed compositions and methods may be used for example, in treating autoimmune diseases, inflammatory disorders, allergies, transplant rejection, cancer, and other immune system disorders.

1 .- 34 . (canceled) 
     
     
         35 . A method for treating a subject, the method comprising:
 administering to a subject having a disorder or needing preventive measures for a disorder an effective amount of a pharmaceutical composition comprising an antibody, wherein the antibody comprises an amino acid sequence as set out in SEQ ID NO: 19, SEQ ID NO: 25, SEQ ID NO: 31, SEQ ID NO: 37, or SEQ ID NO: 52.   
     
     
         36 . The method of  claim 35 , wherein the disorder is an immune disorder or cancer. 
     
     
         37 . The method of  claim 35  wherein the disorder is cancer. 
     
     
         38 . The method of  claim 35  wherein the disorder is an immune disorder selected from the group consisting of:
 an autoimmune disorder, an immune response to a graft, and an allergic reaction.   
     
     
         39 . The method of  claim 35  wherein the disorder is an immune disorder selected from the group consisting of:
 rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosis, type I diabetes, transplant rejection, graft-versus-host disease and hyperproliferative immune disorders.   
     
     
         40 . The method of any one of  claims 35 - 39 , wherein the subject is a human. 
     
     
         41 . The method of any one of  claims 35 - 39 , wherein the antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 47, and SEQ ID NO: 49. 
     
     
         42 . The method of any one of  claims 35 - 39 , wherein the antibody specifically binds to an amino acid sequence that is at least 95% identical to any sequence of at least 100 contiguous amino acids of at least one sequence selected from group consisting of SEQ ID NO: 41 and SEQ ID NO: 56. 
     
     
         43 . The method of  claim 35 , wherein the antibody specifically binds to the extracellular domain of PD-1 with an affinity constant greater than 10 7  M −1 . 
     
     
         44 . The method of  claim 42 , wherein the antibody inhibits the binding of PD-L to PD-1 with an IC 50  of less than 10 nM. 
     
     
         45 . The method of any one of  claims 35 - 39 , wherein the antibody is a human antibody. 
     
     
         46 . The method of  claim 35 , wherein the antibody is IgG1 or IgG4. 
     
     
         47 . The method of  claim 43 , wherein the antibody is IgG1λ or IgG1κ. 
     
     
         48 . The method of any one of  claims 35 - 39 , wherein the antibody is PD1-17, PD1-28, PD1-33, PD1-35, or PD1-F2 
     
     
         49 . The method of any one of  claims 35 - 39 , wherein the antibody is produced by a method of making an antibody that specifically binds to PD-1, wherein the method comprises:
 (a) providing a starting repertoire of nucleic acids encoding a variable domain that either includes a CDR3 to be replaced or lacks a CDR3 encoding region;   (b) combining the repertoire with a donor nucleic acid encoding an amino acid sequence as set out in SEQ ID NO: 19, SEQ ID NO: 25, SEQ ID NO: 31, SEQ ID NO: 37, or SEQ ID NO: 52, such that the donor nucleic acid is inserted into the CDR3 region in the repertoire, so as to provide a product repertoire of nucleic acids encoding a variable domain;   (c) expressing the nucleic acids of the product repertoire;   (d) selecting an antigen-binding fragment specific for PD-1; and   (e) recovering the specific antigen-binding fragment or nucleic acid encoding the binding fragment.