title: Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats.
abstract: The internalizing monoclonal antibody BR96 was conjugated to the anticancer drug doxorubicin (DOX) using an acid-labile hydrazone bond to DOX and a thioether bond to the monoclonal antibody. The resulting conjugate, termed BR96-DOX, binds to a tumor-associated Lewis(y) antigen that is abundantly expressed on the surface of human carcinoma cells. BR96-DOX binds to RCA, a human colon carcinoma cell line, and BN7005, a transplantable colon carcinoma induced in a Brown Norway (BN) rat by 1,2-dimethyl-hydrazine. BR96-DOX produces cures of established s.c. RCA human colon carcinomas in athymic mice and rats. BR96-DOX also cured both s.c. and intrahepatic BN7005 tumors in immunocompetent BN rats. Unconjugated DOX, given at its maximum tolerated dose, and matching doses of nonbinding IgG-DOX conjugate were not active against RCA or BN7005 carcinomas. An anticonjugate antibody response was produced in BN rats treated with BR96-DOX. However, this could be largely prevented by administering the immunosuppressive drug deoxyspergualin. These results confirm the concept of antibody-directed therapy in models in which the targeted antigen is expressed both in normal tissues and tumors. The findings in BN7005 further demonstrate efficacy of BR96-DOX therapy in a model in which the tumor is syngeneic and the host is immunocompetent.
authors.affiliation: Department of Cell and Molecular Biology, University of Lund, Sweden.
authors.forename: H O
authors.initials: HO
authors.lastname: Sjögren
authors.forename: M
authors.initials: M
authors.lastname: Isaksson
authors.forename: D
authors.initials: D
authors.lastname: Willner
authors.forename: I
authors.initials: I
authors.lastname: Hellström
authors.forename: K E
authors.initials: KE
authors.lastname: Hellström
authors.forename: P A
authors.initials: PA
authors.lastname: Trail
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011914:Rats, Inbred BN; D014183:Transplantation, Heterologous; D014185:Transplantation, Isogeneic; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C092612:BR96-doxorubicin immunoconjugate; D000922:Immunotoxins; D004317:Doxorubicin