Antibodies directed against t cell immunoglobulin and mucin protein 3 (tim-3)

Abstract

The invention relates to an isolated immunoglobulin heavy chain polypeptide and an isolated immunoglobulin light chain polypeptide that bind to a protein encoded by the T Cell Immunoglobulin and Mucin Protein-3 (TIM-3). The invention provides a TIM-3-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 TIM-3-binding agent to treat a disorder or disease that is responsive to TIM-3 inhibition, such as cancer, an infectious disease, or an autoimmune disease.

1 . An isolated immunoglobulin heavy chain polypeptide which comprises the amino acid sequence Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Xaa1 Ala Xaa2 Ser Gly Phe Xaa3 Xaa4 Xaa5 Thr Phe Ser Xaa6 Tyr Xaa7 Met Xaa8 Trp Val Arg Gln Ala Xaa9 Gly Lys Gly Leu Xaa10 Trp Val Ser Xaa11 Ile Ser Xaa12 Gly Gly Xaa13 Tyr Thr Tyr Tyr Gln Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Xaa14 Glu Asp Thr Ala Val Tyr Tyr Cys Xaa15 Ser Xaa16 Xaa17 Xaa18 Xaa19 Met Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala (SEQ ID NO: 1), wherein
 (a) Xaa1 is deleted or is alanine (Ala),   (b) Xaa2 is alanine (Ala), proline (Pro), aspartic acid (Asp), glycine (Gly), threonine (Thr), or valine (Val),   (c) the subsequence Xaa3 Xaa4 Xaa5 is deleted or is Thr-Phe-Ile,   (d) Xaa6 is serine (Ser), asparagine (Asn), arginine (Arg), or threonine (Thr),   (e) Xaa7 is aspartic acid (Asp) or alanine (Ala),   (f) Xaa8 is serine (Ser) or threonine (Thr),   (g) Xaa9 is proline (Pro) or leucine (Leu),   (h) Xaa10 is aspartic acid (Asp) or glutamic acid (Glu),   (i) Xaa11 is threonine (Thr) or alanine (Ala),   (j) Xaa12 is glycine (Gly) or serine (Ser),   (k) Xaa13 is serine (Ser), threonine (Thr), aspartic acid (Asp), glycine (Gly), asparagine (Asn), or lysine (Lys),   (l) Xaa14 is alanine (Ala) or valine (Val),   (m) Xaa15 is alanine (Ala) or threonine (Thr), and   (n) the subsequence Xaa16 Xaa17 Xaa18 Xaa19 is deleted or is Pro-Tyr-Tyr-Ala.   
     
     
         2 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , wherein the subsequence Xaa3 Xaa4 Xaa5 is deleted. 
     
     
         3 . The isolated immunoglobulin heavy chain polypeptide of  claim 2 , which comprises the amino acid sequence of any one of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5-SEQ ID NO: 8, SEQ ID NO: 10-SEQ ID NO: 12, SEQ ID NO: 14-SEQ ID NO: 27, or SEQ ID NO: 29-SEQ ID NO: 44. 
     
     
         4 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , wherein the subsequence Xaa3 Xaa4 Xaa5 is Thr-Phe-Ile. 
     
     
         5 . The isolated immunoglobulin heavy chain polypeptide of  claim 4 , which comprises the amino acid sequence of any one of SEQ ID NO: 4, SEQ ID NO: 9, SEQ ID NO: 13, and SEQ ID NO: 28. 
     
     
         6 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , wherein the subsequence Xaa16 Xaa17 Xaa18 Xaa19 is deleted. 
     
     
         7 . The isolated immunoglobulin heavy chain polypeptide of  claim 6 , which comprises the amino acid sequence of any one of SEQ ID NO: 3-SEQ ID NO: 44. 
     
     
         8 . The isolated immunoglobulin heavy chain polypeptide of  claim 1 , wherein the subsequence Xaa16 Xaa17 Xaa18 Xaa19 is Pro-Tyr-Tyr-Ala. 
     
     
         9 . The isolated immunoglobulin heavy chain polypeptide of  claim 8 , which comprises the amino acid sequence of SEQ ID NO: 2. 
     
     
         10 . An isolated immunoglobulin light chain polypeptide which comprises the amino acid sequence Asp Ile Gln Met Thr Xaa1 Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Xaa2 Ser Gln Ser Ile Xaa3 Xaa4 Tyr Leu Asn Trp Tyr Xaa5 Gln Lys Xaa6 Xaa7 Lys Ala Pro Lys Leu Leu Xaa8 Tyr Xaa9 Ala Ser Xaa10 Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Xaa11 Tyr Tyr Cys Gln Gln Xaa12 Xaa13 Xaa14 Xaa15 Pro Xaa16 Thr Phe Gly Xaa17 Gly Thr Lys Xaa18 Glu Ile Lys Arg (SEQ ID NO: 45), wherein
 (a) Xaa1 is glutamine (Gin) or histidine (His),   (b) Xaa2 is alanine (Ala) or threonine (Thr),   (c) Xaa3 is serine (Ser), arginine (Arg), asparagine (Asn), or threonine (Thr),   (d) Xaa4 is serine (Ser), arginine (Arg), aspartic acid (Asp), threonine (Thr), or glycine (Gly),   (e) Xaa5 is glutamine (Gin) or histidine (His),   (f) Xaa6 is proline (Pro) or alanine (Ala),   (g) Xaa7 is glycine (Gly), lysine (Lys), or arginine (Arg),   (h) Xaa8 is isoleucine (Ile) or methionine (Met),   (i) Xaa9 is alanine (Ala), glycine (Gly), aspartic acid (Asp), threonine (Thr), serine (Ser), valine (Val), or isoleucine (Ile),   (j) Xaa10 is serine (Ser) or threonine (Thr),   (k) Xaa11 is valine (Val), methionine (Met), or alanine (Ala)   (l) Xaa12 is serine (ser) or arginine (Arg),   (m) Xaa13 is tyrosine (Tyr), histidine (His), phenylalanine (Phe), aspartic acid (Asp), serine (Ser), or asparagine (Asn),   (n) Xaa14 is serine (Ser) or asparagine (Asn),   (o) Xaa15 is threonine (Thr), serine (Ser), alanine (Ala), or proline (Pro),   (p) Xaa16 is leucine (Leu) or histidine (His),   (q) Xaa17 is glycine (Gly), arginine (Arg), or glutamic acid (Glu), and   (r) Xaa18 is valine (Val) or leucine (Leu).   
     
     
         11 . The isolated immunoglobulin light chain polypeptide of  claim 10 , which comprises the amino acid sequence of any one of SEQ ID NO: 46-SEQ ID NO: 125. 
     
     
         12 . An isolated immunoglobulin heavy chain polypeptide which comprises the amino acid sequence Glu Val Gln Xaa1 Leu Xaa2 Xaa3 Xaa4 Xaa5 Ser Gly Gly Xaa6 Leu Xaa7 Gln Pro Gly Gly Ser Leu Arg Leu Xaa8 Cys Xaa9 Ala Ser Gly Phe Thr Phe Xaa10 Xaa11 Ser Tyr Xaa12 Met Xa13 Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Xaa14 Ile Ser Gly Ser Gly Gly Xaa15 Thr Tyr Tyr Xaa16 Asp Ser Val Lys Gly Xaa17 Phe Thr Ile Ser Xaa18 Asp Asn Ser Xaa19 Asn Thr Xaa20 Tyr Leu Gln Met Asn Xaa21 Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Xaa22 Lys Lys Tyr Tyr Xaa23 Xaa24 Pro Ala Asp Tyr Trp Xaa25 Gln Gly Thr Leu Val Thr Val Ser Ser Gly (SEQ ID NO: 126), wherein
 (a) Xaa1 is leucine (Leu), valine (Val), or methionine (Met),   (b) the subsequence Xaa2 Xaa3 Xaa4 is deleted or is Glu-Ser-Leu,   (c) Xaa5 is deleted or is glutamic acid (Glu),   (d) Xaa6 is glycine (Gly) or aspartic acid (Asp),   (d) Xaa7 is valine (Val) or isoleucine (Ile),   (e) Xaa8 is serine (Ser) or tyrosine (Tyr),   (f) Xaa9 is alanine (Ala) or valine (Val),   (g) Xaa10 is serine (Ser), asparagine (Asn), arginine (Arg), threonine (Thr), aspartic acid (Asp), or glycine (Gly),   (h) Xaa11 is deleted or is glycine (Gly),   (i) Xaa12 is alanine (Ala) or threonine (Thr),   (j) Xaa13 is serine (Ser) or asparagine (Asn),   (k) Xaa14 is alanine (Ala), glycine (Gly), valine (Val), serine (Ser), phenylalanine (Phe), isoleucine (Ile), threonine (Thr), or aspartic acid (Asp),   (l) Xaa15 is serine (Ser) or asparagine (Asn),   (m) Xaa16 is alanine (Ala), valine (Val), or asparagine (Asn),   (n) Xaa17 is arginine (Arg) or glutamine (Gln),   (o) Xaa18 is arginine (Arg) or lysine (Lys),   (p) Xaa19 is lysine (Lys) or asparagine (Asn),   (q) Xaa20 is leucine (Leu), valine (Val), threonine (Thr), methionine (Met), or proline (Pro),   (r) Xaa21 is serine (Ser) or asparagine (Asn),   (s) Xaa22 is alanine (Ala) or glycine (Gly),   (t) Xaa23 is glycine (Gly), valine (Val), aspartic acid (Asp), alanine (Ala), threonine (Thr), or asparagine (Asn),   (u) Xaa24 is glycine (Gly), serine (Ser), valine (Val), aspartic acid (Asp), asparagine (Asn), or threonine (Thr), and   (v) Xaa25 is glycine (Gly) or aspartic acid (Asp).   
     
     
         13 . The isolated immunoglobulin heavy chain polypeptide of  claim 12 , wherein the subsequence Xaa2 Xaa3 Xaa4 is deleted. 
     
     
         14 . The isolated immunoglobulin heavy chain polypeptide of  claim 13 , which comprises the amino acid sequence of any one of SEQ ID NO: 127-SEQ ID NO: 227, SEQ ID NO: 229-SEQ ID NO: 231, SEQ ID NO: 233-SEQ ID NO: 235, SEQ ID NO: 237-SEQ ID NO: 243, or SEQ ID NO: 245-SEQ ID NO: 259. 
     
     
         15 . The isolated immunoglobulin heavy chain polypeptide of  claim 12 , wherein the subsequence Xaa2 Xaa3 Xaa4 is Glu-Ser-Leu. 
     
     
         16 . The isolated immunoglobulin heavy chain polypeptide of  claim 15 , which comprises the amino acid sequence of SEQ ID NO: 228, SEQ ID NO: 232, SEQ ID NO: 236, or SEQ ID NO: 244. 
     
     
         17 . The isolated immunoglobulin heavy chain polypeptide of  claim 12 , wherein Xaa5 is deleted. 
     
     
         18 . The isolated immunoglobulin heavy chain polypeptide of  claim 17 , which comprises the amino acid sequence of any one of SEQ ID NO: 222, SEQ ID NO: 231, SEQ ID NO: 235, or SEQ ID NO: 243. 
     
     
         19 . The isolated immunoglobulin heavy chain polypeptide of  claim 12 , wherein Xaa5 is glutamic acid (Glu). 
     
     
         20 . The isolated immunoglobulin heavy chain polypeptide of  claim 19 , which comprises the amino acid sequence of any one of SEQ ID NO: 126-SEQ ID NO: 221, SEQ ID NO: 223-SEQ ID NO: 230, SEQ ID NO: 232-SEQ ID NO: 234, SEQ ID NO: 236-SEQ ID NO: 242, or SEQ ID NO: 244-SEQ ID NO: 259. 
     
     
         21 . An isolated immunoglobulin light chain polypeptide which comprises the amino acid sequence Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr Leu Xaa1 Trp Tyr Xaa2 Xaa3 Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Xaa4 Gly Val Pro Asp Arg Phe Xaa5 Gly Ser Xaa6 Ser Gly Thr Asp Phe Thr Leu Xaa7 Ile Xaa8 Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Xaa Gln Tyr Tyr Xaa10 Ser Pro Xaa11 Thr Phe Gly Gly Gly Thr Lys Ile Glu Xaa12 Lys (SEQ ID NO: 260), wherein
 (a) Xaa1 is alanine (Ala) or threonine (Thr),   (b) Xaa2 is glutamine (Gln) or histidine (His),   (c) Xaa3 is glutamine (Gln) or histidine (His),   (d) Xaa4 is serine (Ser), tyrosine (Tyr), aspartic acid (Asp), glycine (Gly), threonine (Thr), asparagine (Asn), lysine (Lys), glutamic acid (Glu), leucine (Leu), proline (Pro), or valine (Val),   (e) Xaa5 is serine (Ser) or asparagine (Asn),   (f) Xaa6 is glycine (Gly), glutamic acid (Glu), alanine (Ala), aspartic acid (Asp), asparagine (Asn), serine (Ser), threonine (Thr), or valine (Val),   (g) Xaa7 is threonine (Thr) or isoleucine (Ile),   (h) Xaa8 is serine (Ser) or isoleucine (Ile),   (i) Xaa9 is glutamine (Gln) or histidine (His),   (j) Xaa10 is serine (Ser), asparagine (Asn), arginine (Arg), glycine (Gly), or threonine (Thr),   (k) Xaa11 is leucine (Leu) or isoleucine (Ile), and   (l) Xaa12 is leucine (Leu) or valine (Val).   
     
     
         22 .- 57 . (canceled)