Therapeutic binding agents against MUC-1 antigen and methods for their use

Abstract

The invention provides therapeutic compositions comprising binding agents that specifically bind to tumor-associated MUC-1 and reduce, reverse or prevent their effects in cancer. More particularly, the invention provides therapeutic compositions that comprise a binding agent that can specifically bind to an epitope that comprises both peptide and carbohydrate on such tumor-associated MUC-1. The invention further provides methods for the use of such therapeutic compositions in the treatment of cancer.

1 . A therapeutic composition consisting essentially of a non-radiolabeled binding agent that specifically binds to an epitope of tumor-associated MUC-1 and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1.  
     
     
         2 . A therapeutic composition comprising a binding agent, other than HMFG1, that specifically binds to an epitope of tumor-associated MUC-1 and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1.  
     
     
         3 . A therapeutic composition comprising a binding agent that specifically binds to both soluble and tumor-bound tumor-associated MUC-1 and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1.  
     
     
         4 . The therapeutic composition according to  claim 2 , wherein the binding agent is not a monoclonal antibody selected from: HMPV, VU-3-C6, MF06, VU-11-D1, MF30, BCP8, DF3, BC2, B27.29, VU-3-D1, 7540MR, MF11, Bc4E549, VU-11-E2, M38, E29, GP1.4, 214D4, BC4W154, HMFG-2, C595, Mc5 and A76-A/C7.  
     
     
         5 - 37 . (Cancelled).  
     
     
         38 . A method for therapeutically treating a mammal bearing a tumor, the method comprising administering to the mammal an effective amount of a binding agent according to  claim 3 .  
     
     
         39 . (Cancelled)  
     
     
         40 . The therapeutic composition according to  claim 1  wherein the binding agent induces an anti-idiotype response and a cellular immune response in the mammal.  
     
     
         41 . The therapeutic composition according to  claim 2  wherein the binding agent induces an anti-idiotype response and a cellular immune response in the mammal.  
     
     
         42 . The therapeutic composition according to  claim 3  wherein the binding agent induces an anti-idiotype response and a cellular immune response in the mammal.  
     
     
         43 . A binding agent that binds immunological determinants from amino acid residues of a peptide having the amino acid sequence DTRPAP.  
     
     
         44 . A binding agent which binds the same epitope as Alt-1.  
     
     
         45 . Alt-1.  
     
     
         46 . A therapeutic composition comprising a binding agent selected from the group consisting of the binding agent according to  claim 43 .  
     
     
         47 . A therapeutic composition comprising a binding agent selected from the group consisting of the binding agent according to  claim 44 .  
     
     
         48 . A therapeutic composition comprising a binding agent selected from the group consisting of the binding agent according to  claim 45 .  
     
     
         49 . A therapeutic composition comprising an activated binding agent that specifically binds to an epitope of tumor-associated MUC-1 and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1.  
     
     
         50 . The therapeutic composition according to  claim 43 , wherein the binding agent is photoactivated.  
     
     
         51 . The therapeutic composition according to  claim 44 , wherein the binding agent is photoactivated.  
     
     
         52 . The therapeutic composition according to  claim 45 , wherein the binding agent is photoactivated.  
     
     
         53 . The therapeutic composition according to  claim 2 , wherein the binding agent is coupled to a photodynamic agent.  
     
     
         54 . The therapeutic composition according to  claim 53 , wherein photodynamic agents include hypocrellins and hypocrellin derivatives.  
     
     
         55 . The therapeutic composition according to  claim 1 , wherein the epitope comprises an immunological determinant that includes carbohydrate.  
     
     
         56 . The therapeutic composition according to  claim 2 , wherein the epitope comprises an immunological determinant that includes carbohydrate.  
     
     
         57 . A method for therapeutically treating a mammal bearing a tumor, the method comprising administering to the mammal an effective amount of a therapeutic composition according to any one of claims  1 - 4 ,  40 - 42  and  46 - 54 .  
     
     
         58 . A method for therapeutically treating a mammal bearing a tumor, the method comprising administering to the mammal an effective amount of a therapeutic composition comprising a binding agent that specifically binds to an epitope of tumor-associated MUC-1 and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1, wherein the effective amount is a dosage of less than about 8 mg/30 kg body weight.  
     
     
         59 . A method for therapeutically treating a mammal bearing a tumor, the method comprising intravenously administering to the mammal an effective amount of a therapeutic composition comprising a binding agent that specifically binds to an epitope of tumor-associated MUC-1 and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1.  
     
     
         60 . A method for therapeutically treating a mammal bearing a tumor, the method comprising subcutaneously administering to the mammal an effective amount of a therapeutic composition comprising a binding agent that specifically binds to an epitope of tumor-associated MUC-1 and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1.  
     
     
         61 . A method for therapeutically treating a mammal bearing a tumor, wherein the animal has a baseline level of anti-MUC-1 antibody, the method comprising subcutaneously administering to the mammal an amount of a therapeutic composition comprising a binding agent that specifically binds to an epitope of tumor-associated MUC-1 that causes an increase of at least 3-fold in anti-MUC-1 antibody compared to the baseline level and that is effective in therapeutically treating a mammal having a tumor that expresses a tumor-associated MUC-1.  
     
     
         62 . The method according to  claim 57 , wherein the binding agent is administered intravenously.  
     
     
         63 . The method according to  claim 57 , wherein the binding agent is administered subcutaneously.  
     
     
         64 . The method according to  claim 58 , wherein the binding agent is administered intravenously.  
     
     
         65 . The method according to  claim 58 , wherein the binding agent is administered subcutaneously.  
     
     
         66 . The method according to  claim 57 , wherein the effective amount is less than 8 mg/30 kg body weight.  
     
     
         67 . The method according to  claim 66 , wherein the binding agent is administered at a dosage of less than about 3 mg/30 kg body weight.  
     
     
         68 . The method according to  claim 67 , wherein the binding agent is administered at a dosage of about 2 mg/patient.  
     
     
         69 . The method according to  claim 67 , wherein the binding agent is administered at a dosage of from about 0.5 to about 2 mg/30 kg body weight.  
     
     
         70 . The method according to  claim 69 , wherein the binding agent is administered at a dosage of from about 0.5 to about 1.5 mg/30 kg body weight.  
     
     
         71 . The method according to  claim 70 , wherein the binding agent is administered at a dosage of about 1 mg/30 kg body weight.  
     
     
         72 . The method according to  claim 57 , wherein the binding agent is administered at a dosage that is the maximum amount of binding agent that does not induce antibody-mediated toxicity.  
     
     
         73 . The method according to  claim 57 , wherein the binding agent is administered at a dosage that is the maximum amount of binding agent that does not produce ADCC or CDC.  
     
     
         74 . The method according to  claim 57 , wherein the binding agent is administered at a dosage that elicits a HAXA response >200 U/ml.  
     
     
         75 . The method according to  claim 74 , wherein the binding agent is administered at a dosage that elicits a HAXA response >2000 U/ml.  
     
     
         76 . The method according to  claim 74 , wherein the HAXA response is a HAMA response.  
     
     
         77 . The method according to  claim 57 , wherein the binding agent is administered at a dosage that reduces the level of tumor antigen CA15.3  
     
     
         78 . The method according to  claim 75 , further comprising irradiating the mammal with a visible light source.  
     
     
         79 . The method according to any one of claims  58 - 60  and  64 - 65 , wherein the effective amount is less than 8 mg/30 kg body weight.  
     
     
         80 . The method according to  claim 79 , wherein the binding agent is administered at a dosage of less than about 3 mg/30 kg body weight.  
     
     
         81 . The method according to  claim 80 , wherein the binding agent is administered at a dosage of about 2 mg/patient.  
     
     
         82 . The method according to  claim 80 , wherein the binding agent is administered at a dosage of from about 0.5 to about 2 mg/30 kg body weight.  
     
     
         83 . The method according to  claim 82 , wherein the binding agent is administered at a dosage of from about 0.5 to about 1.5 mg/30 kg body weight.  
     
     
         84 . The method according to  claim 83 , wherein the binding agent is administered at a dosage of about 1 mg/30 kg body weight.  
     
     
         85 . The method according to any one of claims  58 - 60  and  64 - 65 , wherein the binding agent is administered at a dosage that is the maximum amount of binding agent that does not induce antibody-mediated toxicity.  
     
     
         86 . The method according to any one of claims  58 - 60  and  64 - 65 , wherein the binding agent is administered at a dosage that is the maximum amount of binding agent that does not produce ADCC or CDC.  
     
     
         87 . The method according to any one of claims  58 - 60  and  64 - 65 , wherein the binding agent is administered at a dosage that elicits a HAXA response >200 U/ml.  
     
     
         88 . The method according to  claim 87 , wherein the binding agent is administered at a dosage that elicits a HAXA response >2000 U/ml.  
     
     
         89 . The method according to  claim 87 , wherein the HAXA response is a HAMA response.  
     
     
         90 . The method according to any one of claims  58 - 60  and  64 - 65 , wherein the binding agent is administered at a dosage that reduces the level of tumor antigen CA15.3.  
     
     
         91 . The method according to  claim 59  wherein the binding agent is administered in the absence of an adjuvant.  
     
     
         92 . The method according to claims  58  or  65 , wherein the binding agent is administered in the presence of an adjuvant.  
     
     
         93 . A method for therapeutically treating a mammal bearing a tumor, the method comprising administering to the mammal an effective amount of a therapeutic composition according to  claim 53  or  54 .  
     
     
         94 . The method according to  claim 57 , wherein the binding agent binds both circulating and tumor-bound MUC-1.