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Experimental Therapeutics

Antitumor Activity of Carcinoma-reactive BR96-Doxorubicin Conjugate against Human Carcinomas in Athymic Mice and Rats and Syngeneic Rat Carcinomas in Immunocompetent Rats

Hans Olov Sjögren, M. Isaksson, David Willner, Ingegerd Hellström, Karl Erik Hellström and Pamela A. Trail
Hans Olov Sjögren
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M. Isaksson
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David Willner
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Ingegerd Hellström
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Karl Erik Hellström
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Pamela A. Trail
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DOI:  Published October 1997
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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 Lewisy 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 immuno-suppressive 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.

Footnotes

  • ↵1 This work was supported by the Bristol Myers Squibb Pharmaceutical Research Institute and the Swedish Medical Research Council.

  • ↵2 To whom requests for reprints should be addressed, at Unit of Tumor Immunology, Department of Cell and Molecular Biology, Wallenberg Laboratory, Box 7031, 220 07 Lund, Sweden.

  • Received February 5, 1997.
  • Accepted August 7, 1997.
  • ©1997 American Association for Cancer Research.
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October 1997
Volume 57, Issue 20
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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
Hans Olov Sjögren, M. Isaksson, David Willner, Ingegerd Hellström, Karl Erik Hellström and Pamela A. Trail
Cancer Res October 15 1997 (57) (20) 4530-4536;

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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
Hans Olov Sjögren, M. Isaksson, David Willner, Ingegerd Hellström, Karl Erik Hellström and Pamela A. Trail
Cancer Res October 15 1997 (57) (20) 4530-4536;
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