T cell receptors and immune therapy using the same against prame positive cancers

Abstract

The present invention pertains to antigen recognizing constructs against tumor associated antigens (TAA), in particular against Preferentially Expressed Antigen of Melanoma (PRAME). The invention in particular provides novel T cell receptor (TCR) based molecules which are selective and specific for the tumor expressed antigen of the invention. The TCR of the invention, and TAA binding fragments derived therefrom, are of use for the diagnosis, treatment and prevention of TAA expressing cancerous diseases. Further provided are nucleic acids encoding the antigen recognizing constructs of the invention, vectors comprising these nucleic acids, recombinant cells expressing the antigen recognizing constructs and pharmaceutical compositions comprising the compounds of the invention.

1 . An antigen recognizing construct comprising at least one complementary determining region (CDR) 3 having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NOs. 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63, 69, 75, 81, 129, and 135. 
     
     
         2 . The antigen recognizing construct according to  claim 1 , wherein said antigen recognizing construct is capable of specifically and/or selectively binding to Preferentially Expressed Antigen of Melanoma (PRAME) antigenic peptide consisting of the amino acid sequence selected from SEQ ID NO: 97-115 in a complex with HLA-A*02. 
     
     
         3 . The antigen recognizing construct according to  claim 1 , wherein the antigen recognizing construct is an antibody, or derivative or fragment thereof, or a T cell receptor (TCR), or a derivative or fragment thereof. 
     
     
         4 . The antigen recognizing construct according to  claim 1 , comprising a TCR α or γ chain; and/or a TCR β or δ chain; wherein the TCR α or γ chain comprises a CDR3 having at least 80% sequence identity to an amino acid sequence selected from SEQ ID Nos. 3, 15, 27, 39, 51, 63, 75, and 129 and/or wherein the TCR β or δ chain comprises a CDR3 having at least 80% sequence identity to an amino acid sequence selected from SEQ ID Nos. 9, 21, 33, 45, 57, 69, 81, and 135. 
     
     
         5 . The antigen recognizing construct according to  claim 4 , wherein the TCR α or γ chain further comprises a CDR1 having at least 80% sequence identity to an amino acid sequence selected from SEQ ID Nos. 1, 13, 25, 37, 49, 61, 73, and 127; and/or a CDR2 having at least 80% sequence identity to an amino acid sequence selected from SEQ ID Nos. 2, 14, 26, 38, 50, 62, 74, 128, 196, 197, 198, 199, 200, 201, 202, and 204. 
     
     
         6 . The antigen recognizing construct according to  claim 4 , wherein the TCR β or δ chain further comprises a CDR1 having at least 80% sequence identity to an amino acid sequence selected from SEQ ID Nos. 7, 19, 31, 43, 55, 67, 79, and 133; and/or a CDR2 having at least 80% sequence identity to an amino acid sequence selected from SEQ ID Nos. 8, 20, 32, 44, 56, 68, 80, and 134. 
     
     
         7 . The antigen recognizing construct according to  claim 1 , comprising a TCR variable chain region having at least 80% sequence identity to an amino acid sequence selected from SEQ ID Nos. 4, 10, 16, 22, 28, 34, 40, 46, 52, 58, 64, 70, 76, 82, 130, and 136. 
     
     
         8 . The antigen recognizing construct according to  claim 1 , comprising a binding fragment of a TCR, and wherein said binding fragment comprises CDR1 to CDR3 optionally selected from the CDR1 to CDR3 sequences having the amino acid sequences of SEQ ID Nos. 1, 2, 3, 196; or 7, 8, 9; or 13, 14, 15, 197; or 19, 20, 21; or 25, 26, 27, 198; or 31, 32, 33; or 37, 38, 39, 199; or 43, 44, 45; or 49, 50, 51, 200; or 55, 56, 57; or 61, 62, 63, 201; or 67, 68, 69; or 73, 74, 75, 202; or 79, 80, 81; or 127, 128, 129, 204; or 133, 134, 135. 
     
     
         9 . A nucleic acid encoding for the antigen recognizing construct according to  claim 1 . 
     
     
         10 . A vector comprising the nucleic acid according to  claim 9 . 
     
     
         11 . A host cell comprising the vector of  claim 10 . 
     
     
         12 . The host cell of  claim 11 , wherein the host cell is a T lymphocyte. 
     
     
         13 . The host cell of  claim 12 , wherein the T lymphocyte is a CD4-positive cell or a CD8-positive T-cell. 
     
     
         14 . A pharmaceutical composition comprising the antigen recognizing construct according to  claim 1 , a pharmaceutical acceptable carrier, stabilizer, and/or excipient. 
     
     
         15 . A method of treating a patient who has a PRAME positive cancer, comprising administering to the patient a population of transformed CD8+ T cells expressing the antigen recognizing construct according to  claim 1 ,
 wherein the antigen recognizing construct is capable of binding to a peptide consisting of the amino acid sequence selected from SEQ ID NO: 97-115 in a complex with HLA-A*02, and   wherein the cancer is selected from acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, cancer of the oral cavity, cancer of the vagina, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, glioma, Hodgkin lymphoma, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, cancer of the oropharynx, ovarian cancer, cancer of the penis, pancreatic cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer, skin cancer, small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, cancer of the uterus, ureter cancer, and urinary bladder cancer.   
     
     
         16 . The method of  claim 15 , wherein the population of transformed cells are administered in the form of a pharmaceutical composition comprising a chemotherapeutic agent selected from the group consisting of asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, and vincristine. 
     
     
         17 . The method of  claim 15 , wherein the cancer is melanoma. 
     
     
         18 . The method of  claim 15 , wherein the cancer is bone cancer. 
     
     
         19 . A method of manufacturing a tumor associated antigen (TAA) specific antigen recognizing construct expressing cell line, comprising
 a. providing a suitable host cell,   b. providing a genetic construct comprising a coding sequence encoding the antigen recognizing construct according to  claim 1 ,   c. introducing into said suitable host cell said genetic construct, and   d. expressing said genetic construct by said suitable host cell.   
     
     
         20 . The method according to  claim 19 , further comprising isolating and purifying the antigen recognizing construct from the suitable host cell and, optionally, reconstituting the antigen recognizing construct in a T lymphocyte.