T cell receptors recognizing mhc class ii-restricted mage-a3

Abstract

The invention provides an isolated or purified T-cell receptor (TCR) having antigenic specificity for MHC Class II-restricted MAGE-A3. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a mammal are further provided by the invention.

1 - 2 . (canceled) 
     
     
         3 . The antibody, or antigen binding portion thereof, of  claim 32 , wherein the TCR or functional variant comprises:
 (i) SEQ ID NO: 29, wherein
 Xaa4 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa5 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa6 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa7 is Thr, Ala, Leu, Ile, Val, or Met; 
   and/or (ii) SEQ ID NO: 30, wherein
 Xaa4 is Arg, Ala, Leu, Ile, Val, or Met; 
 Xaa5 is Thr, Ala, Leu, Ile, Val, or Met; 
 Xaa6 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa7 is Pro, Ala, Leu, Ile, Val, or Met. 
   
     
     
         4 . The antibody, or antigen binding portion thereof, of  claim 3 , wherein the functional variant comprises: (a) SEQ ID NO: 29, wherein Xaa4 is Ala, Xaa5 is Ser, Xaa6 is Gly, and Xaa7 is Thr, or (b) SEQ ID NO: 29, wherein Xaa4 is Ser, Xaa5 is Ala, Xaa6 is Gly, and Xaa7 is Thr. 
     
     
         5 . The antibody, or antigen binding portion thereof, of  claim 32 , wherein the TCR or functional variant comprises a murine constant region. 
     
     
         6 . The antibody, or antigen binding portion thereof, of  claim 5 , wherein the TCR or functional variant comprises a murine constant region comprising SEQ ID NO: 25 and/or SEQ ID NO: 26. 
     
     
         7 . The antibody, or antigen binding portion thereof, of  claim 32 , wherein the TCR or functional variant comprises:
 a first amino acid sequence selected from the group consisting of
 (i) SEQ ID NO: 31, wherein
 Xaa116 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa117 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa118 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa119 is Thr, Ala, Leu, Ile, Val, or Met; and 
 
 (ii) SEQ ID NO: 9; 
   and a second amino acid sequence selected from the group consisting of
 (i) SEQ ID NO: 32, wherein
 Xaa115 is Arg, Ala, Leu, Ile, Val, or Met; 
 Xaa116 is Thr, Ala, Leu, Ile, Val, or Met; 
 Xaa117 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa118 is Pro, Ala, Leu, Ile, Val, or Met; and 
 
 (ii) SEQ ID NO: 10. 
   
     
     
         8 . The antibody, or antigen binding portion thereof, of  claim 7 , wherein the functional variant comprises:
 (a) SEQ ID NO: 31, wherein Xaa116 is Ala, Xaa117 is Ser, Xaa118 is Gly, and Xaa119 is Thr, or   (b) SEQ ID NO: 31, wherein Xaa116 is Ser, Xaa117 is Ala, Xaa118 is Gly, and Xaa119 is Thr.   
     
     
         9 . The antibody, or antigen binding portion thereof, of  claim 3 , wherein the TCR or functional variant comprises:
 a first amino acid sequence selected from the group consisting of
 (i) SEQ ID NO: 33, wherein
 Xaa116 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa117 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa118 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa119 is Thr, Ala, Leu, Ile, Val, or Met; 
 
 (ii) SEQ ID NO: 11; 
 (iii) SEQ ID NO: 21; and 
 (iv) SEQ ID NO: 27; 
   and a second amino acid sequence selected from the group consisting of
 (i) SEQ ID NO: 34, wherein
 Xaa115 is Arg, Ala, Leu, Ile, Val, or Met; 
 Xaa116 is Thr, Ala, Leu, Ile, Val, or Met; 
 Xaa117 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa118 is Pro, Ala, Leu, Ile, Val, or Met; 
 
 (ii) SEQ ID NO: 12; 
 (iii) SEQ ID NO: 22; and 
 (iv) SEQ ID NO: 28. 
   
     
     
         10 . The antibody, or antigen binding portion thereof, of  claim 9 , wherein the functional variant comprises:
 (a) SEQ ID NO: 33, wherein Xaa116 is Ala, Xaa117 is Ser, Xaa118 is Gly, and Xaa119 is Thr, or   (b) SEQ ID NO: 33, wherein Xaa116 is Ser, Xaa117 is Ala, Xaa118 is Gly, and Xaa119 is Thr.   
     
     
         11 - 31 . (canceled) 
     
     
         32 . An antibody, or antigen binding portion thereof, which specifically binds to a functional portion of a TCR or functional variant of the TCR, wherein the TCR and functional variant have antigenic specificity for MAGE-A3 243-258  and MAGE-A6 and the functional portion comprises
 (a) SEQ ID NOs: 3, 4, 6, 7,
 (i) SEQ ID NO: 29, wherein
 Xaa4 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa5 is Ser, Ala, Leu, Ile, Val, or Met; 
 Xaa6 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa7 is Thr, Ala, Leu, Ile, Val, or Met; and 
 
 (ii) SEQ ID NO: 30, wherein
 Xaa4 is Arg, Ala, Leu, Ile, Val, or Met; 
 Xaa5 is Thr, Ala, Leu, Ile, Val, or Met; 
 Xaa6 is Gly, Ala, Leu, Ile, Val, or Met; and 
 Xaa7 is Pro, Ala, Leu, Ile, Val, or Met; or 
 
   (b) SEQ ID NOs: 3-8.   
     
     
         33 . A pharmaceutical composition comprising the antibody, or antigen binding portion thereof, of  claim 32 , and a pharmaceutically acceptable carrier. 
     
     
         34 . A method of detecting the presence of cancer in a mammal, comprising:
 (a) contacting a sample comprising one or more cells from the mammal with the the antibody, or antigen binding portion thereof, of  claim 32 , thereby forming a complex, and   (b) detecting the complex, wherein detection of the complex is indicative of the presence of cancer in the mammal.   
     
     
         35 . The method of  claim 34 , wherein the cancer is melanoma, breast cancer, lung cancer, prostate cancer, synovial cell sarcoma, head and neck cancer, esophageal cancer, or ovarian cancer. 
     
     
         36 . A method of treating or preventing cancer in a mammal, the method comprising administering to the mammal the antibody, or antigen binding portion thereof, of  claim 32 , in an amount effective to treat or prevent cancer in the mammal. 
     
     
         37 . The method according to  claim 36 , wherein the cancer is melanoma, breast cancer, lung cancer, prostate cancer, synovial cell sarcoma, head and neck cancer, esophageal cancer, or ovarian cancer.