Antibody-drug conjugate comprising antibody against human ror1 and use for the same

Abstract

The present invention relates to new antibody-drug conjugates (ADCs) targeting ROR1, active metabolites of such ADCs, methods for preparation of such ADCs, uses for such ADCs in treatment and/or prevention of illnesses, and uses for such ADCs in production of drugs for treatment and/or prevention of diseases, more specifically diseases associated with over-expression of ROR1, for example cancer. More specifically, the present invention relates to an antibody-drug conjugate comprising an antibody that binds to ROR1 or an antigen-binding fragment thereof, and a pharmaceutical composition comprising the same.

1 - 139 . (canceled) 
     
     
         140 . An antibody-drug conjugate represented by I or a pharmaceutically acceptable salt thereof:
   A b —(X) y   [Formula I]
   wherein   Ab is an anti-ROR1 antibody comprising a heavy chain variable region comprising a CDRH1, a CDRH2, and a CDRH3; and a light chain variable region comprising a CDRL1, a CDRL2 and a CDRL3; wherein
 CDRH1 comprises the amino acid sequence of SEQ ID NOs: 4; 
 CDRH2 comprises the amino acid sequence of SEQ ID NOs: 11; 
 CDRH3 comprises the amino acid sequence of SEQ ID NOs: 19; 
 CDRL1 comprises the amino acid sequence of SEQ ID NOs: 27; 
 CDRL1 comprises the amino acid sequence of SEQ ID NOs: 35; 
 CDRL1 comprises the amino acid sequence of SEQ ID NOs: 42; 
   X is   
       
         
           
           
               
               
           
         
            is bonded to Ab; and 
         y is 2. 
       
     
     
         141 . The antibody-drug conjugate of  claim 140 , wherein the antibody comprises a heavy chain variable region having either:
 i) a sequence according to SEQ ID NO: 48; or   ii) a sequence having at least 90% or at least 95% or more homology to the amino acid sequence of SEQ ID NO: 48.   
     
     
         142 . The antibody-drug conjugate of  claim 140 , wherein the antibody comprises a light chain variable region having either:
 i) a sequence according to SEQ ID NO: 56; or   ii) a sequence having at least 90% or at least 95% or more homology to the amino acid sequence of SEQ ID NO: 56.   
     
     
         143 . The antibody-drug conjugate of  claim 140 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 48 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56. 
     
     
         144 . The antibody-drug conjugate of  claim 140 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 64 and a light chain comprising the amino acid sequence of SEQ ID NO: 72. 
     
     
         145 . The antibody-drug conjugate of  claim 140 , wherein: the antibody is an IgG1 fully human monoclonal antibody and the ROR1 is human ROR1 or mouse ROR1. 
     
     
         146 . The antibody-drug conjugate of  claim 140 , wherein the antibody is bonded to X via a thioether bond; the thioether bond includes a sulfur atom of the cysteine of the antibody; and the antibody comprises an amino acid motif which can be recognized by isoprenoid transferase at the C-terminus of the antibody. 
     
     
         147 . The antibody-drug conjugate of  claim 146 , wherein the amino acid motif has the sequence of CVIM. 
     
     
         148 . The antibody-drug conjugate of  claim 140 , wherein the antibody-drug conjugate has a structure according to: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         149 . A method of treating a disease or disorder associated with the over-expression of ROR1 in a subject, comprising administering an antibody-drug conjugate of  claim 140 . 
     
     
         150 . The method of  claim 149 , wherein the disease is cancer. 
     
     
         151 . The method of  claim 150 , wherein the cancer is chronic lymphocytic leukemia (CLL), B-cell leukemia, lymphoma, acute myeloid leukemia (AML), Burkitt lymphoma, mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL), breast cancer, renal cancer, ovarian cancer, gastric cancer, liver cancer, lung cancer, colorectal cancer, pancreatic cancer, skin cancer, bladder cancer, testicular cancer, uterine cancer, prostate cancer, non-small cell lung cancer (NSCLC), neuroblastoma, brain cancer, colon cancer, squamous cell carcinoma, melanoma, myeloma, cervical cancer, thyroid cancer, head and neck cancer or adrenal cancer. 
     
     
         152 . The pharmaceutical composition according to  claim 149 , wherein the pharmaceutical composition further comprises a pharmaceutically efficacious amount of a chemotherapeutic agent. 
     
     
         153 . A method of treating cancer in a subject, comprising administering an antibody drug conjugate of  claim 149  to the subject. 
     
     
         154 . The method of  claim 153 , wherein the cancer is chronic lymphocytic leukemia (CLL), B-cell leukemia, lymphoma, acute myeloid leukemia (AML), Burkitt lymphoma, mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), Diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL), breast cancer, renal cancer, ovarian cancer, gastric cancer, liver cancer, lung cancer, colorectal cancer, pancreatic cancer, skin cancer, bladder cancer, testicular cancer, uterine cancer, prostate cancer, non-small cell lung cancer (NSCLC), neuroblastoma, brain cancer, colon cancer, squamous cell carcinoma, melanoma, myeloma, cervical cancer, thyroid cancer, head and neck cancer or adrenal cancer. 
     
     
         155 . The pharmaceutical composition according to  claim 154 , wherein the pharmaceutical composition further comprises a pharmaceutically efficacious amount of a chemotherapeutic agent.