Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents

Abstract

The present invention is based on the discovery that the administration of at least one immunoconjugate and at least one chemotherapeutic agent provides an unexpectedly superior treatment for cancer. The present invention is directed to compositions comprising at least one immunoconjugate and at least one chemotherapeutic agent and to methods of treating cancer using at least one immunoconjugate and at least one chemotherapeutic agent. The present invention also provides methods of modulating the growth of selected cell populations, such as cancer cells, by administering a therapeutically effective amount of at least one chemotherapeutic agent and at least one immunoconjugate.

1. A pharmaceutical composition comprising a synergistic combination of at least one chemotherapeutic agent and at least one immunoconjugate; wherein the immunoconjugate comprises at least one maytansinoid compound linked to a monoclonal antibody or fragment thereof; wherein the monoclonal antibody or fragment thereof binds to an antigen expressed by a cancer cell, and wherein the chemotherapeutic agent is a taxane compound, an epothilone compound, a platinum compound, an epipodophyllotoxin compound, a camptothecin compound, or a mixture of two or more thereof. 
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the chemotherapeutic agent is a taxane compound, a platinum compound, an epipodophyllotoxin compound, a camptothecin compound, or a mixture of two or more thereof. 
     
     
       3. The pharmaceutical composition of  claim 1 , wherein the chemotherapeutic agent is paclitaxel, docetaxel, epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, epothilone F, cisplatin, carboplatin, oxaliplatin, iproplatin, ormaplatin, tetraplatin, etoposide, teniposide, camptothecin, topotecan, irinotecan, 9-aminocamptothecin, or a mixture of two or more thereof. 
     
     
       4. The pharmaceutical composition of  claim 1 , wherein the chemotherapeutic agent is paclitaxel, cisplatin, etoposide, docetaxel, topotecan, or a mixture of two or more thereof. 
     
     
       5. The pharmaceutical composition of  claim 1 , wherein the monoclonal antibody or fragment thereof binds to a CD56 antigen. 
     
     
       6. The pharmaceutical composition of  claim 1 , wherein the monoclonal antibody or fragment thereof is at least one of Fv, Fab, Fab′ or F(ab′) 2 . 
     
     
       7. The pharmaceutical composition of  claim 1 , wherein the monoclonal antibody or fragment thereof is humanized N901. 
     
     
       8. The pharmaceutical composition of  claim 1 , wherein the monoclonal antibody or fragment thereof is humanized C242. 
     
     
       9. The pharmaceutical composition of  claim 1 , wherein the immunoconjugate comprises at least one maytansinoid compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein is Z 0  is H or SR; R is methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic; t is 1, 2 or 3; Y 0  is chlorine or hydrogen; and X 3  is hydrogen or methyl. 
     
     
       10. The pharmaceutical composition of  claim 9 , wherein Z 0  is H; t is 2; Y 0  is chlorine; and X 3  is methyl. 
     
     
       11. The pharmaceutical composition of  claim 1 , wherein the immunoconjugate is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein MAb is a monoclonal antibody or fragment thereof that binds to an antigen expressed by the cancer cell. 
     
     
       12. A pharmaceutical composition comprising a synergistic combination of at least one chemotherapeutic agent and at least one immunoconjugate; wherein the chemotherapeutic agent is a taxane compound, an epothilone compound, a platinum compound, an epipodophyllotoxin compound, a camptothecin compound, or a mixture of two or more thereof; and wherein the immunoconjugate is: 
       
         
           
           
               
               
           
         
       
       wherein MAb is a monoclonal antibody or fragment thereof that binds to an antigen expressed by a cancer cell. 
     
     
       13. A pharmaceutical composition comprising a synergistic combination of (i) at least one chemotherapeutic agent selected from the group consisting of paclitaxel, docetaxel, cisplatin, etoposide, topotecan and irinotecan and (ii) an immunoconjugate comprising a maytansinoid and a humanized monoclonal antibody selected from the group consisting of N901 and C242. 
     
     
       14. The pharmaceutical composition of  claim 13 , wherein the maytansinoid is a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein Z 0  is H or SR; wherein R is methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic; t is 1, 2 or 3; Y 0  is chlorine or hydrogen; and X 3  is hydrogen or methyl. 
     
     
       15. A pharmaceutical composition comprising a synergistic combination of (i) at least one chemotherapeutic agent selected from the group consisting of paclitaxel, docetaxel, cisplatin, etoposide, topotecan and irinotecan and (ii) an immunoconjugate comprising a maytansinoid and a humanized monoclonal antibody or fragment thereof that binds to an antigen expressed by a small cell lung cancer cell, a non small cell lung cancer cell or a colorectal cancer cell. 
     
     
       16. The pharmaceutical composition of  claim 15 , wherein the maytansinoid is a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       wherein Z 0  is H or SR; wherein R is methyl, linear alkyl, branched alkyl, cyclic alkyl, simple or substituted aryl or heterocyclic; t is 1, 2 or 3; Y 0  is chlorine or hydrogen; and X 3  is hydrogen or methyl. 
     
     
       17. An immunoconjugate comprising a cell binding agent and a maytansinoid, wherein the cell binding agent is conjugated to the maytansinoid using N-succinimidyl-4-[2-pyridyldithio]-pentanoate (SPP), and wherein the cell binding agent is a humanized N901 monoclonal antibody or an antigen binding fragment thereof. 
     
     
       18. The immunoconjugate of claim 17, wherein the cell binding agent is a humanized N901 monoclonal antibody. 
     
     
       19. The immunoconjugate of claim 17, wherein the cell binding agent is an Fv, Fab, Fab′, or F(ab′) 2  fragment of a humanized N901 monoclonal antibody. 
     
     
       20. The immunoconjugate of claim 17, wherein the maytansinoid is DM1. 
     
     
       21. A pharmaceutical composition comprising the immunoconjugate of claim 17 and a pharmaceutically acceptable carrier.