Antibodies Directed Against Programmed Death-1(PD-1)

Abstract

The invention relates to an isolated immunoglobulin heavy chain polypeptide and an isolated immunoglobulin light chain polypeptide that bind to a programmed death-1 (PD-1) protein. The invention provides a PD-1-binding agent that comprises the aforementioned immunoglobulin heavy chain polypeptide and immunoglobulin light chain polypeptide. The invention also provides related vectors, compositions, and methods of using the PD-1-binding agent to treat a cancer or an infectious disease.

1 . An isolated immunoglobulin heavy chain or light chain polypeptide, wherein the polypeptide comprises:
 (I) an immunoglobulin heavy chain polypeptide which comprises a complementarity determining region 1 (CDR) amino acid sequence of SEQ ID NO: 1, a CDR2 amino acid sequence of SEQ ID NO: 2, and a CDR3 amino acid sequence of SEQ ID NO: 3, wherein optionally   (a) residue 9 of SEQ ID NO: 1 is replaced with a different amino acid residue,   (b) one or more of residues 7, 8, and 9 of SEQ ID NO: 2 is replaced with a different amino acid residue,   (c) one or more of residues 1, 2, and 5 of SEQ ID NO: 3 is replaced with a different amino acid residue, or   (d) any combination of (a)-(c);   (II) an isolated immunoglobulin heavy chain polypeptide which comprises a complementarity determining region 1 (CDR) amino acid sequence of SEQ ID NO: 12, a CDR2 amino acid sequence of SEQ ID NO: 13, and a CDR3 amino acid sequence of SEQ ID NO: 14, wherein optionally   (a) residue 9 of SEQ ID NO: 12 is replaced with a different amino acid residue,   (b) residue 8 and/or residue 9 of SEQ ID NO: 13 is replaced with a different amino acid residue,   (c) residue of SEQ ID NO: 14 is replaced with a different amino acid residue, or   (d) any combination of (a)-(c);   or   (III) an isolated immunoglobulin heavy chain polypeptide which comprises a complementarity determining region 1 (CDR) amino acid sequence of SEQ ID NO: 19, a CDR2 amino acid sequence of SEQ ID NO: 20, and a CDR3 amino acid sequence of SEQ ID NO: 21;   or   (IV) an isolated immunoglobulin light chain polypeptide which comprises a complementarity determining region 1 (CDR) amino acid sequence of SEQ ID NO: 26 and a CDR2 amino acid sequence of SEQ ID NO: 27;   or   (V) an isolated immunoglobulin light chain polypeptide which comprises a complementarity determining region 1 (CDR) amino acid sequence of SEQ ID NO: 30 and a CDR2 amino acid sequence of SEQ ID NO: 31, wherein optionally residue 12 of SEQ ID NO: 30 is replaced with a different amino acid residue;   or   (VI) an isolated immunoglobulin light chain polypeptide which comprises a complementarity determining region 1 (CDR) amino acid sequence of SEQ ID NO: 35, a CDR2 amino acid sequence of SEQ ID NO: 36, and a CDR3 amino acid sequence of SEQ ID NO: 37, wherein optionally   (a) residue 5 of SEQ ID NO: 36 is replaced with a different amino acid residue, and/or   (b) residue 4 of SEQ ID NO: 37 is replaced with a different amino acid residue;   or   (VII) an isolated immunoglobulin heavy chain polypeptide which comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 4-11, SEQ ID NOs: 15-18, SEQ ID NOs: 22-25; SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, or SEQ ID NO: 41.   
     
     
         2 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 1, a CDR2 amino acid sequence of SEQ ID NO: 2, and a CDR3 amino acid sequence of SEQ ID NO: 3, except that residue 9 of SEQ ID NO: 1 is replaced with a methionine (M) residue. 
     
     
         3 . (canceled) 
     
     
         4 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 1, a CDR2 amino acid sequence of SEQ ID NO: 2, and a CDR3 amino acid sequence of SEQ ID NO: 3, except that
 (a) residue 7 of SEQ ID NO: 2 is replaced with an asparagine (N) residue,   (b) residue 8 of SEQ ID NO: 2 is replaced with a serine (S) residue,   (c) residue 9 of SEQ ID NO: 2 is replaced with a threonine (T) residue, or   (d) any combination of(a)-(c).   
     
     
         5 . (canceled) 
     
     
         6 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 1, a CDR2 amino acid sequence of SEQ ID NO: 2, and a CDR3 amino acid sequence of SEQ ID NO: 3, except that
 (a) residue 1 of SEQ ID NO: 3 is replaced with a glutamic acid (E) residue,   (b) residue 2 of SEQ ID NO: 3 is replaced with a tyrosine (Y) residue,   (c) residue 5 of SEQ ID NO: 3 is replaced with a serine (S) residue, or   (d) any combination of (a)-(c).   
     
     
         7 .- 9 . (canceled) 
     
     
         10 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 12, a CDR2 amino acid sequence of SEQ ID NO: 13, and a CDR3 amino acid sequence of SEQ ID NO: 14, except that residue 9 of SEQ ID NO: 12 is replaced with a leucine (L) residue. 
     
     
         11 . (canceled) 
     
     
         12 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 12, a CDR2 amino acid sequence of SEQ ID NO: 13, and a CDR3 amino acid sequence of SEQ ID NO: 14, except that
 (a) residue 8 of SEQ ID NO: 13 is replaced with a tyrosine (Y) residue, and/or   (b) residue 9 of SEQ ID NO: 13 is replaced with an alanine (A) residue.   
     
     
         13 . (canceled) 
     
     
         14 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 12, a CDR2 amino acid sequence of SEQ ID NO: 13, and a CDR3 amino acid sequence of SEQ ID NO: 14, except that residue 5 of SEQ ID NO: 3 is replaced with a threonine (T) residue. 
     
     
         15 .- 23 . (canceled) 
     
     
         24 . The isolated immunoglobulin light chain polypeptide of  claim 1 , wherein the polypeptide comprises a complementarity determining region 1 (CDR) amino acid sequence of SEQ ID NO: 30 and a CDR2 amino acid sequence of SEQ ID NO: 31, except that residue 12 of SEQ ID NO: 30 is replacedwith a threonine (T) residue. 
     
     
         25 .- 26 . (canceled) 
     
     
         27 . The isolated immunoglobulin light chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 35, a CDR2 amino acid sequence of SEQ ID NO: 36, and a CDR3 amino acid sequence of SEQ ID NO: 37, except that residue 5 of SEQ ID NO: 36 is replaced with a leucine (L) residue. 
     
     
         28 . (canceled) 
     
     
         29 . The isolated immunoglobulin light chain polypeptide of  claim 1 , which comprises a CDR1 amino acid sequence of SEQ ID NO: 35, a CDR2 amino acid sequence of SEQ ID NO: 36, and a CDR3 amino acid sequence of SEQ ID NO: 37, except that residue 4 of SEQ ID NO: 37 is replaced with an asparagine (N) residue. 
     
     
         30 . (canceled) 
     
     
         31 . The isolated immunoglobulin heavy chain or light chain polypeptide of  claim 1 , which comprises an amino acid sequence of SEQ ID NOs: 4-11, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 38, SEQ IS NO. 39, SEQ ID NO: 40, or SEQ ID NO: 41. 
     
     
         32 . (canceled) 
     
     
         33 . An isolated or purified nucleic acid sequence encoding the isolated immunoglobulin heavy chain or light chain polypeptide of  claim 1 , optionally in a vector. 
     
     
         34 .- 35 . (canceled) 
     
     
         36 . An isolated programmed death-1 protein (PD-1)-binding agent comprising an immunoglobulin heavy chain polypeptide and an immunoglobulin light chain polypeptide of  claim 1 . 
     
     
         37 . The isolated PD-1-binding agent of  claim 36 , which is an antibody, an antibody conjugate, or an antigen-binding fragment thereof. 
     
     
         38 . The isolated PD-1-binding agent of  claim 36 , which is an antibody fragment selected from F(ab′)2, Fab′, Fab, Fv, scFv, dsFv, dAb, and a single chain binding polypeptide. 
     
     
         39 . An isolated or purified nucleic acid sequence encoding the PD-1-binding agent of  claim 36 , optionally in a vector. 
     
     
         40 . (canceled) 
     
     
         41 . An isolated cell comprising the nucleic acid, optionally in a vector, of  claim 39 . 
     
     
         42 . A composition comprising the isolated PD-1-binding agent of  claim 36  and a pharmaceutically acceptable carrier. 
     
     
         43 . A method of treating a cancer or an infectious disease in a mammal, which method comprises administering an effective amount of the composition of  claim 42  to a mammal having a cancer or an infectious disease, whereupon the cancer or infectious disease is treated in the mammal. 
     
     
         44 .- 48 . (canceled) 
     
     
         49 . The method of  claim 43 , wherein (a) the half-life of the PD-1-binding agent in the mammal is between 30 minutes and 45 days; (b) the PD-1-binding agent binds to PD-1 with a KD between about 1 picomolar (pM) and about 100 micromolar (μM): or both (a) and (b). 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 43 , further comprising administering to the mammal a composition comprising (i) an antibody that binds to a TIM-3 protein and (ii) a pharmaceutically acceptable carrier; or (i) an antibody that binds to a LAG-3 protein and (ii) a pharmaceutically acceptable carrier. 
     
     
         52 . (canceled)