Recombinant anti-cd30 antibodies and uses thereof

Abstract

The present invention relates to methods and compositions for the treatment of Hodgkin's Disease, comprising administering proteins characterized by their ability to bind to CD30, or compete with monoclonal antibodies AC10 or HeFi-1 for binding to CD30, and exert a cytostatic or cytotoxic effect on Hodgkin's disease cells in the absence of effector cells or complement. Such proteins include derivatives of monoclonal antibodies AC10 and HeFi-1. The proteins of the invention can be human, humanized, or chimeric antibodies; further, they can be conjugated to cytotoxic agents such as chemotherapeutic drugs. The invention further relates to nucleic acids encoding the proteins of the invention. The invention yet further relates to a method for identifying an anti-CD30 antibody useful for the treatment or prevention of Hodgkin's Disease.

1 . An antibody-drug conjugate, in which the antibody is conjugated to a drug via a linker, and wherein the antibody:
 (a) immunospecifically binds CD30,   (b) exerts a cytostatic or cytotoxic effect on a Hodgkin's Disease cell line, which cytostatic or cytotoxic effect is complement-independent and achieved in the absence of:
 (i) conjugation to a cytostatic or cytotoxic agent, and 
 (ii) effector cells, and 
   (c) is not monoclonal antibody AC10 or HeFi-1 and does not result from cleavage of AC10 or HeFi-1 with papain or pepsin; wherein if the antibody is derived from antibody HeFi-1, it is a humanized HeFi-1 antibody;   
       and wherein the linker of the formula:
   -T a -W w —Y y    
   wherein:   -T- is a stretcher unit;   a is 0 or 1;   each —W— is independently an amino acid unit;   w is independently an integer ranging from 2 to 12;   —Y— is a spacer unit; and   y is 0, 1 or 2.   
 
     
     
         2 . The antibody-drug conjugate of  claim 1  wherein the antibody comprises a human constant domain. 
     
     
         3 . The antibody-drug conjugate of  claim 1  wherein the antibody is purified. 
     
     
         4 . The antibody-drug conjugate of  claim 1  wherein the antibody competes for binding to CD30 with monoclonal antibody AC10 or HeFi-1. 
     
     
         5 . The antibody-drug conjugate of  claim 1  wherein the antibody is a fusion protein comprising the amino acid sequence of a second protein that is not an antibody. 
     
     
         6 . The antibody-drug conjugate of  claim 1  wherein the drug is an auristatin. 
     
     
         7 . The antibody-drug conjugate of  claim 6  wherein the drug is MMAE. 
     
     
         8 . An antibody-drug conjugate, in which the antibody is chimeric or humanized and is conjugated to a drug via a linker, and wherein the antibody comprises:
 (a) a heavy chain variable region comprising complementarity determining regions having the amino acid sequences of SEQ ID NO:4, SEQ ID NO:6 and SEQ ID NO:8; and   (b) a light chain variable region comprising complementarity determining regions having the amino acid sequences of SEQ ID NO:12, SEQ ID NO:14 and SEQ ID NO: 16;   
       and wherein the linker of the formula:
   -T a -W w —Y y    
   wherein:   -T- is a stretcher unit;   a is 0 or 1;   each —W— is independently an amino acid unit;   w is independently an integer ranging from 2 to 12;   —Y— is a spacer unit; and   y is 0, 1 or 2.   
 
     
     
         9 . The antibody-drug conjugate of  claim 8  wherein the antibody is cAC10. 
     
     
         10 . The antibody-drug conjugate of  claim 8  wherein the drug is a dolastatin. 
     
     
         11 . The antibody-drug conjugate of  claim 8  wherein the drug is an auristatin. 
     
     
         12 . The antibody-drug conjugate of  claim 8  wherein the drug is selected from at least one of the group consisting of MMAE, AEB, AEVB, and AEFP. 
     
     
         13 . The antibody-drug conjugate of  claim 12  wherein the drug is MMAE. 
     
     
         14 . The antibody-drug conjugate of  claim 9  wherein the drug is MMAE. 
     
     
         15 . The antibody-drug conjugate of  claim 8  wherein the amino acid sequence of the heavy chain variable region of the antibody is at least 90% identical to SEQ ID NO:2, and the amino acid sequence of the light chain variable region of the antibody is at least 90% identical to SEQ ID NO:10. 
     
     
         16 . The antibody-drug conjugate of  claim 15  wherein the antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NO:2 and SEQ ID NO:10, respectively. 
     
     
         17 . The antibody-drug conjugate of  claim 16  wherein the antibody comprises a human IgG1 constant region having the amino acid sequence set forth in SEQ ID NO.33 and a human light chain kappa constant region having the amino acid sequence set forth in SEQ ID NO.34. 
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         19 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody-drug conjugate of  claim 8 , and a pharmaceutically acceptable carrier.