Different toxicity profiles for drug- versus radionuclide-conjugated BR96 monoclonal antibodies in a syngeneic rat colon carcinoma model

Abstract

Background. One of many approaches being evaluated in experimental models and in the clinic for the treatment of cancer is the use of antibodies conjugated to various drugs or radionuclides. The aim of the present study was to compare the toxicity profiles of radioimmunoconjugates and drug-immunoconjugates based on the same monoclonal antibody, evaluated in the same experimental model, that much resembles human studies. The pattern of dose-limiting toxicity of a monomethylauristatin-conjugated monoclonal antibody (BR96) was compared to that of the same antibody conjugated with lutetium-177, and to the same non-conjugated antibody. Material and methods. Rats with established colon carcinoma were injected with monomethylauristatin-conjugated mAb-BR96, ¹⁷⁷Lu-BR96, or non-conjugated BR96. Liver, kidney, and myelotoxicity were assessed for 100 days by analysis of blood parameters. Body weight and therapeutic effects was also monitored. Results. Myelotoxicity was found to be dose limiting for the radionuclide BR96 conjugate. The dose-limiting factor was prolonged suppression of leukocytes (>28 days) with increased risk of infections. For monomethylauristatin-conjugated BR96, liver toxicity was dose limiting, whereas no dose-limiting toxicity was observed with non-conjugated BR96. Both the drug-immunoconjugate and the radioimmunoconjugate resulted in decreased platelet counts, but the time to nadir and duration differed. Conclusion. The two conjugates resulted in different patterns of toxicity. By using the two conjugates of BR96 in a sequential therapeutic design it could be possible to increase the therapeutic window and hence probably the efficacy without significantly increasing the toxicity. This concept is regarded as valid regardless of conjugate or model chosen.

Acknowledgements

We would like to thank Dr. Peter Senter (Seattle Genetics, Seattle, WA, USA) for kindly providing the monoclonal antibody BR96 and the auristatin-BR96 conjugate. The research was supported by grants from the Swedish Cancer Society, Mrs. Berta Kamprad's Foundation, Gunnar Nilsson's Foundation, Lund University Medical Faculty Foundation, and The Lund University Hospital Fund. The authors have no affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this publication.