Anti-wt1/hla-specific antibodies

Abstract

The present invention relates to antibodies or fragments thereof binding to human WT1/HLA. In particular, the present invention relates to antibodies or fragments thereof that have combined improved and/or beneficial properties, and are therefore suited for clinical development.

1 . An isolated antibody comprising
 (a) a heavy chain comprising an HCDR1 region consisting of SEQ ID NO: 17, an HCDR2 region consisting of SEQ ID NO: 18, an HCDR3 region consisting of SEQ ID NO: 19, and a light chain comprising a LCDR1 region consisting of SEQ ID NO: 20, a LCDR2 region consisting of SEQ ID NO: 21, and a LCDR3 region consisting of SEQ ID NO: 22, or   (b) a heavy chain comprising an HCDR1 region consisting of SEQ ID NO: 27, an HCDR2 region consisting of SEQ ID NO: 28, an HCDR3 region consisting of SEQ ID NO: 29, and a light chain comprising a LCDR1 region consisting of SEQ ID NO: 30, a LCDR2 region consisting of SEQ ID NO: 31, and a LCDR3 region consisting of SEQ ID NO: 32, or   (c) a heavy chain comprising an HCDR1 region consisting of SEQ ID NO: 37, an HCDR2 region consisting of SEQ ID NO: 38, an HCDR3 region consisting of SEQ ID NO: 39, and a light chain comprising a LCDR1 region consisting of SEQ ID NO: 40, a LCDR2 region consisting of SEQ ID NO: 41, and a LCDR3 region consisting of SEQ ID NO: 42, or   (d) a heavy chain comprising an HCDR1 region consisting of SEQ ID NO: 47, an HCDR2 region consisting of SEQ ID NO: 48, an HCDR3 region consisting of SEQ ID NO: 49, and a light chain comprising a LCDR1 region consisting of SEQ ID NO: 50, a LCDR2 region consisting of SEQ ID NO: 51, and a LCDR3 region consisting of SEQ ID NO: 52, or   (e) a heavy chain comprising an HCDR1 region consisting of SEQ ID NO: 57, an HCDR2 region consisting of SEQ ID NO: 58, an HCDR3 region consisting of SEQ ID NO: 59, and a light chain comprising a LCDR1 region consisting of SEQ ID NO: 60, a LCDR2 region consisting of SEQ ID NO: 61, and a LCDR3 region consisting of SEQ ID NO: 62,
 wherein said antibody specifically binds to a complex of HLA-A0201/RMFPNAPYL (SEQ ID NO: 1). 
   
     
     
         2 . The isolated antibody of  claim 1 , wherein
 (a) the heavy chain comprises a heavy chain variable region (VH) comprising at least 95% sequence identity to SEQ ID NO: 15, and the light chain comprises a light chain variable region (VL) comprising at least 95% sequence identity to SEQ ID NO: 16, or   (b) the heavy chain comprises a heavy chain variable region (VH) comprising at least 95% sequence identity to SEQ ID NO: 25, and the light chain comprises a light chain variable region (VL) comprising at least 95% sequence identity to SEQ ID NO: 26, or   (c) the heavy chain comprises a heavy chain variable region (VH) comprising at least 95% sequence identity to SEQ ID NO: 35, and the light chain comprises a light chain variable region (VL) comprising at least 95% sequence identity to SEQ ID NO: 36, or   (d) the heavy chain comprises a heavy chain variable region (VH) comprising at least 95% sequence identity to SEQ ID NO: 45, and the light chain comprises a light chain variable region (VL) comprising at least 95% sequence identity to SEQ ID NO: 46, or   (e) the heavy chain comprises a heavy chain variable region (VH) comprising at least 95% sequence identity to SEQ ID NO: 55, and the light chain comprises a light chain variable region (VL) comprising at least 95% sequence identity to SEQ ID NO: 56.   
     
     
         3 . The isolated antibody of  claim 1 , wherein
 (a) the heavy chain comprises a heavy chain variable region (VH) comprising SEQ ID NO: 15, and the light chain comprises a light chain variable region (VL) comprising SEQ ID NO: 16, or   (b) the heavy chain comprises a heavy chain variable region (VH) comprising SEQ ID NO: 25, and the light chain comprises a light chain variable region (VL) comprising SEQ ID NO: 26, or   (c) the heavy chain comprises a heavy chain variable region (VH) comprising SEQ ID NO: 35, and the light chain comprises a light chain variable region (VL) SEQ ID NO: 36, or   (d) the heavy chain comprises a heavy chain variable region (VH) comprising SEQ ID NO: 45, and the light chain comprises a light chain variable region (VL) comprising SEQ ID NO: 46, or   (e) the heavy chain comprises a heavy chain variable region (VH) comprising SEQ ID NO: 55, and the light chain comprises a light chain variable region (VL) comprising SEQ ID NO: 56.   
     
     
         4 . The antibody of  claim 1 , wherein the antibody is in an Fab format. 
     
     
         5 . The antibody of  claim 4 , wherein the antibody has an EC50 of less than 10 nM. 
     
     
         6 . The antibody of  claim 1 , wherein the antibody is in an immunoglobulin format. 
     
     
         7 . The antibody of  claim 4 , wherein the antibody has an EC50 of less than 10 nM. 
     
     
         8 . The antibody of  claim 1 , wherein the antibody binds to the complex of HLA-A0201/RMFPNAPYL (SEQ ID NO: 1) with a dissociation rate of less than 0.5 nM. 
     
     
         9 . The antibody of  claim 1 , wherein the antibody is humanized. 
     
     
         10 . The antibody of  claim 1 , wherein said antibody binds to a complex of a peptide consisting of RMFPNAPYL (SEQ ID NO: 1) with HLA-A0201 with an EC50 that is at least 10 times lower than the EC50 for a complex of a peptide consisting of RMFPGEVAL (SEQ ID NO: 64) with HLA-A0201. 
     
     
         11 . The antibody of  claim 1 , wherein said antibody does not bind a complex of a peptide consisting of RMFPGEVAL (SEQ ID NO: 64) with HLA-A0201. 
     
     
         12 . The antibody of  claim 1 , wherein said antibody has an EC50 of less than 10 nM in a Fab format and in an immunoglobulin format. 
     
     
         13 . The antibody of  claim 1 , further comprising a cytotoxic moiety linked thereto. 
     
     
         14 . A pharmaceutical composition comprising the antibody according to  claim 1 , and a pharmaceutically acceptable carrier and/or excipient. 
     
     
         15 . An isolated antibody or an antigen-binding fragment thereof which specifically binds to a complex of HLA-A0201/RMFPNAPYL (SEQ ID NO: 1), wherein said antibody or antigen-binding fragment thereof comprises:
 (a) a heavy chain variable region (VH) comprising CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 15, and a light chain variable region (VL) comprising CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 16, or   (b) a heavy chain variable region (VH) comprising CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 25, and a light chain variable region (VL) comprising CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 26, or   (c) a heavy chain variable region (VH) comprising CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 35, and a light chain variable region (VL) comprising CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 36, or   (d) a heavy chain variable region (VH) comprising CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 45, and a light chain variable region (VL) comprising CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 46, or   (e) a heavy chain variable region (VH) comprising CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 55, and a light chain variable region (VL) comprising CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 56.   
     
     
         16 . The isolated antibody or an antigen-binding fragment thereof of  claim 15 , wherein
 (a) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 15 comprise the amino acid sequences of SEQ ID NO: 17, 18, and 19, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 16 comprise the amino acid sequences of SEQ ID NO: 20, 21, and 22, respectively, or   (b) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 25 comprise the amino acid sequences of SEQ ID NO: 27, 28, and 29, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 26 comprise the amino acid sequences of SEQ ID NO: 30, 31, and 32, respectively, or   (c) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 35 comprise the amino acid sequences of SEQ ID NO: 37, 38, and 39, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 36 comprise the amino acid sequences of SEQ ID NO: 40, 41, and 42, respectively, or   (d) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 45 comprise the amino acid sequences of SEQ ID NO: 47, 48, and 49, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 46 comprise the amino acid sequences of SEQ ID NO: 50, 51, and 52, respectively, or   (e) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 55 comprise the amino acid sequences of SEQ ID NO: 57, 58, and 59, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 56 comprise the amino acid sequences of SEQ ID NO: 60, 61, and 62, respectively.   
     
     
         17 . The isolated antibody or an antigen-binding fragment thereof of  claim 15 , wherein
 (a) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 15 consist of the amino acid sequences of SEQ ID NO: 17, 18, and 19, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 16 consist of the amino acid sequences of SEQ ID NO: 20, 21, and 22, respectively, or   (b) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 25 consist of the amino acid sequences of SEQ ID NO: 27, 28, and 29, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 26 consist of the amino acid sequences of SEQ ID NO: 30, 31, and 32, respectively, or   (c) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 35 consist of the amino acid sequences of SEQ ID NO: 37, 38, and 39, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 36 consist of the amino acid sequences of SEQ ID NO: 40, 41, and 42, respectively, or   (d) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 45 consist of the amino acid sequences of SEQ ID NO: 47, 48, and 49, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 46 consist of the amino acid sequences of SEQ ID NO: 50, 51, and 52, respectively, or   (e) the CDR regions HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 55 consist of the amino acid sequences of SEQ ID NO: 57, 58, and 59, respectively, and the CDR regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 56 consist of the amino acid sequences of SEQ ID NO: 60, 61, and 62, respectively.   
     
     
         18 . The isolated antibody or an antigen-binding fragment thereof of  claim 15 , wherein the antibody or an antigen-binding fragment thereof is in an Fab format. 
     
     
         19 . The isolated antibody or an antigen-binding fragment thereof of  claim 15 , wherein the antibody or an antigen-binding fragment thereof is in an immunoglobulin format. 
     
     
         20 . A method of treating a patent who has cancer that presents RMFPNAPYL (SEQ ID NO: 1) in a complex with HLA-A0201, comprising administering to the patient the antibody of  claim 1 , wherein the cancer is selected from the group consisting of chronic myelocytic leukemia, multiple myeloma, acute lymphoblastic leukemia, acute myeloid/myelogenous leukemia, myelodysplastic syndrome, mesothelioma, ovarian cancer, gastrointestinal cancers, breast cancer, prostate cancer, and glioblastoma.