Cripto Blocking Antibodies and Uses Thereof

Abstract

The invention provides Cripto blocking antibodies, or biologically functional fragments thereof, and uses thereof. Antibodies which bind Cripto and modulate Cripto signaling are provided. Antibodies which bind Cripto and block the interaction between Cripto and ALK4 are provided. Antibodies which bind Cripto and modulate tumor growth are also provided. Antibodies which bind Cripto, modulate signaling, and modulate tumor growth are also provided. Antibodies which bind Cripto, block the interaction between Cripto and ALK4 and modulate tumor growth are provided. The invention also provides methods of using these antibodies in therapeutic, diagnostic, and research applications.

1 - 61 . (canceled) 
     
     
         62 . A method of treating cancer in a subject having cancer cells that over-express Cripto-1 as compared to non-cancerous cells, comprising administering to said subject a therapeutically effective amount of a monoclonal antibody or fragment thereof that binds a Cripto-1, whereby growth or spread of cancer cells in the subject is inhibited and wherein the mechanism of inhibition of growth or spread of the cancer cells is through:
 (a) apoptosis induced by binding of the antibody or fragment thereof to the Cripto-1; or   (b) cytotoxicity induced by delivery to cancer cells of a cytotoxic compound conjugated to said monoclonal antibody or fragment thereof.   
     
     
         63 . The method of  claim 62 , wherein the monoclonal antibody or fragment thereof is a human monoclonal antibody or fragment thereof. 
     
     
         64 . The method of  claim 62 , wherein the monoclonal antibody or fragment thereof is a chimeric monoclonal antibody or fragment thereof. 
     
     
         65 . The method of  claim 62 , wherein the cancer is a colon cancer. 
     
     
         66 . The method of  claim 62 , wherein the cancer is a breast cancer. 
     
     
         67 . The method of  claim 62 , wherein the cancer is a prostate cancer. 
     
     
         68 . The method of  claim 62 , wherein the cancer is a leukemia. 
     
     
         69 . The method of  claim 62 , wherein the cancer is a lung cancer. 
     
     
         70 . The method of  claim 62 , wherein the antibody or fragment thereof induces apoptosis of cancer cells. 
     
     
         71 . The method of  claim 70 , wherein the antibody or fragment thereof induces apoptosis through activation of a JNK or p38 kinase cascade. 
     
     
         72 . The method of  claim 62 , wherein the antibody or fragment thereof binds to an antigenic determinant of a Cripto-1 protein comprising the amino acid sequence of SEQ ID NO: 1 or an EGF-like domain region of SEQ ID NO: 1, or amino acids 75-112, 75-85, 80-90, 85-95, 90-100, 95-105, 100-110, or 105-112 of SEQ ID NO: 1. 
     
     
         73 . The method of  claim 62 , wherein the mechanism of inhibition of grow or spread of cancer cells is apoptosis. 
     
     
         74 . The method of  claim 62 , wherein the mechanism of inhibition of growth or spread of cancer cells is cytotoxicity. 
     
     
         75 . The method of  claim 74 , wherein the antibody or fragment thereof is conjugated to a cytotoxic compound. 
     
     
         76 . The method of  claim 75 , wherein the cytotoxic compound is selected from the group consisting of anthracyclines, 5-fluorouracil, topoisomerase inhibitors, cisplatin, carboplatin and taxol. 
     
     
         77 . The method of  claim 76 , wherein the cytotoxic compound is an anthracycline selected from the group consisting of idarubicin, doxorubicin, daunorubicin and epirubicin. 
     
     
         78 . The method of  claim 77 , wherein the cytotoxic compound is the topoisomerase inhibitor irinotecan. 
     
     
         79 . The method of  claim 62 , wherein the mechanism of inhibition of growth or spread of the cancer cells is through apoptosis induced by binding of the antibody or fragment thereof to the Cripto-1. 
     
     
         80 . The method of  claim 62 , wherein the mechanism of inhibition of growth or spread of the cancer cells is through cytotoxicity induced by delivery to cancer cells of a cytotoxic compound conjugated to said monoclonal antibody or fragment thereof.