Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof

Abstract

Methods for improved targeting of antibody, antibody fragments, peptides hormones, steroid hormones and conjugates thereof are disclosed. Enhanced delivery to target cells of antibodies or fragments thereof or other receptor-mediated delivery system, such as peptide, specific for a population of cells of a mammal comprises steps of administering to said mammal an adequate dosage of blocking antibodies or fragments thereof or other receptor-mediated delivery system, such as peptide, and administering to said mammal an effective dosage of said antibodies or fragments thereof or other receptor-mediated delivery system, such as peptide, specific for said population of cells. In the preferred embodiment, the specific antibodies are monoclonal antibodies directed toward tumor-associated antigen in man.

We claim:  
     
       1. A method of enhancing delivery to solid tumor target cells within a mammal of conjugated specific antibodies or fragments thereof pharmaceutically active and specific for said target cells, comprising the steps of: 
       administering to said mammal an adequate dosage of blocking antibodies or fragments thereof, said blocking antibodies being capable of blocking the binding of the conjugated specific antibodies or fragments thereof to non-target tissue(s) through antigen recognition; and then  
       administering to said mammal a diagnostically or  therapeutically effective dosage of said conjugated specific antibodies or fragments thereof, said conjugated specific antibodies being specific for said solid tumor target cells.  
     
     
       2. The method of  claim 1  wherein said blocking antibodies or fragments thereof are capable of cross-reactive, epitope-specific binding to non-target cells. 
     
     
       3. The method of  claim 1  wherein said antibody fragments are selected from the group consisting of F(ab)′, F(ab)′ 2 , Fab, Fv, and mixtures thereof. 
     
     
       4. The method of  claim 1  wherein said solid tumor target cells are characterized by having tumor-associated antigen. 
     
     
       5. The method of  claim 1  wherein any of the antibodies are monoclonal antibodies. 
     
     
       6. The method of  claim 1  wherein any of the antibodies are polyclonal antibodies. 
     
     
       7. The method of  claim 1  wherein the conjugated specific antibodies comprise antibodies or fragments thereof specific for said target cells conjugated to a cytotoxin. 
     
     
       8. The method of  claim 1  wherein the conjugated specific antibodies comprise antibodies or fragments thereof specific for said target cells conjugated to a radionuclide. 
     
     
       9. The method of  claim 1  wherein the effective dosage of conjugated specific antibodies or fragments thereof is diagnostically effective. 
     
     
       10. The method of  claim 1  wherein the effective dosage of conjugated specific antibodies or fragments thereof is therapeutically effective. 
     
     
       11. The method of  claim 1  wherein the mammal is a human. 
     
     
       12. The method of enhancing the localization at a solid tumor target site of conjugated specific antibodies or fragments thereof specific for an antigen contained on the target site and also on a non-target tissue or organ within a mammal, comprising the steps of: 
       perfusing said non-target tissue or organ with an adequate dosage of blocking antibodies or fragments thereof, said blocking antibodies being capable of blocking the binding of the conjugated specific antibodies or fragments thereof to non-target tissue(s) or organ through antigen recognition; and  
       administering to the mammal a diagnostically or therapeutically effective dosage of said conjugated specific antibodies or fragments thereof specific for said antigen.  
     
     
       13. The method of  claim 12  wherein said blocking antibodies or fragments thereof are capable of cross-reactive, epitope-specific binding to the non-target tissue or organ. 
     
     
       14. The method of  claim 12  wherein said antibody fragments are selected from the group consisting of F(ab)′, F(ab)′ 2 , Fab, Fv, and mixtures thereof. 
     
     
       15. The method of  claim 12  wherein said tissue or organ is characterized by having tumor-associated antigen. 
     
     
       16. The method of  claim 12  wherein the antibodies are monoclonal antibodies. 
     
     
       17. The method of  claim 12  wherein the antibodies are polyclonal antibodies. 
     
     
       18. The method of  claim 12  wherein the conjugated specific antibodies comprise antibodies or fragments thereof conjugated to a cytotoxin or drug . 
     
     
       19. The method of  claim 12  wherein the conjugated specific antibodies comprise antibodies or fragments thereof conjugated to a radionuclide. 
     
     
       20. The method of  claim 12  wherein the blocking antibodies or fragments thereof and the conjugated specific antibodies or fragments thereof are administered simultaneously. 
     
     
       21. The method of  claim 12  wherein the blocking antibodies or fragments thereof are administered prior to the conjugated specific antibodies or fragments thereof. 
     
     
       22. The method of  claim 12  wherein the effective dosage of said conjugated specific antibodies or fragments thereof is diagnostically effective. 
     
     
       23. The method of  claim 12  wherein the effective dosage of said conjugated specific antibodies or fragments thereof is therapeutically effective. 
     
     
       24. The method of  claim 12  wherein the mammal is a human. 
     
     
       25. The method of targeting  treating melanoma in humans, comprising the steps of: 
       administering to said human an adequate dosage of unlabeled specific antibody or fragment thereof that binds to a melanoma-associated antigen; and then  
       administering to said human a diagnostically  or therapeutically effective dose of labeled specific antibody or fragment thereof that binds to the same epitope of the melanoma-associated antigen as the unlabeled specific antibody.  
     
     
       26. The method of  claim 25  wherein the antibody or fragment thereof that binds to a melanoma-associated antigen recognized the 250 Kd. blycoprotein/proteoglycan. 
     
     
       27. The method of  claim 25  wherein the antigen-binding region of the antibody or fragment thereof is selected from the group consisting of antigen-binding regions of antibodies 9.2.27 and NR-ML-05, and their clones, chimaeras and derivatives. 
     
     
       28. The method of  claim 25  wherein the antigen-binding region of the antibody or fragment thereof recognizes the G D3  glycolipid melanoma-associated antigen. 
     
     
       29. The method of  claim 25  wherein the antigen-binding region of antibody or fragment thereof recognizes the P97 melamona-associated antigen. 
     
     
       30. A method of enhancing delivery to solid tumor target cells within a mammal of conjugated specific antibodies or fragments thereof pharmaceutically active and specific for said target cells, comprising the steps of: 
       administering to said mammal an adequate dosage of blocking antibodies or fragments thereof; wherein said blocking antibodies are the unconjugated form of the conjugated specific antibodies or fragments thereof; and then  
       administering to said mammal a diagnostically or  therapeutically effective dosage of said conjugated specific antibodies or fragments thereof, and conjugated specific antibodies being specific for said solid tumor target cells.  
     
     
       31. The method of  claim 30  wherein the conjugated specific antibodies comprise antibodies or fragments thereof specific for said target cells conjugated to a radionuclide. 
     
     
       32. A method of enhancing delivery to tumor target cells within a mammal of conjugated specific antibodies or fragments thereof pharmaceutically active and specific for said target cells, comprising the steps of: 
       
         administering to said mammal an adequate dosage of antibodies or fragments thereof, wherein said antibodies bind to melanoma, colon cancer or lymphoma target cells, and wherein said antibodies are the unconjugated form of the conjugated specific antibodies or fragments thereof; and then  
       
       
         administering to said mammal a therapeutically effective dosage of said conjugated specific antibodies or fragments thereof, said conjugated specific antibodies being specific for said tumor target cells. 
       
     
     
       33. The method of  claim 1  or  32  wherein the conjugated specific antibodies are conjugated to a radioisotope. 
     
     
       34. The method  claim 33  wherein the radioisotope is  131   I.   
     
     
       35. The method of  claim 1  or  30 , wherein the target cells are melanoma cells, colon carcinoma cells, or lymphoma cells.