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Antitumor activity of carcinoma-reactive BR96-doxorubicin conjugate against human carcinomas in athymic mice and rats and syngeneic rat carcinomas in immunocompetent rats.

Authors
  • Sjögren, H O
  • Isaksson, M
  • Willner, D
  • Hellström, I
  • Hellström, K E
  • Trail, P A
Type
Published Article
Journal
Cancer research
Publication Date
Oct 15, 1997
Volume
57
Issue
20
Pages
4530–4536
Identifiers
PMID: 9377565
Source
Medline
License
Unknown

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.

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