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Toxicity-reducing potential of extracorporeal affinity adsorption treatment in combination with the auristatin-conjugated monoclonal antibody BR96 in a syngeneic rat tumor model†
Article first published online: 2 FEB 2010
Copyright © 2010 American Cancer Society
Supplement: Cancer Therapy With Antibodies and Immunoconjugates, Supplement to Cancer
Volume 116, Issue Supplement 4, pages 1033–1042, 15 February 2010
How to Cite
Nilsson, R., Mårtensson, L., Eriksson, S. E., Sjögren, H.-O. and Tennvall, J. (2010), Toxicity-reducing potential of extracorporeal affinity adsorption treatment in combination with the auristatin-conjugated monoclonal antibody BR96 in a syngeneic rat tumor model. Cancer, 116: 1033–1042. doi: 10.1002/cncr.24790
The articles in this supplement were presented at the “12th Conference on Cancer Therapy with Antibodies and Immunoconjugates,” in Parsippany, New Jersey, October 16-18, 2008.
- Issue published online: 2 FEB 2010
- Article first published online: 2 FEB 2010
- Manuscript Accepted: 21 OCT 2009
- Manuscript Received: 9 JUL 2009
- colon carcinoma;
Antibody-drug conjugates, comprising monoclonal antibodies (MoAbs) that bind to tumor-associated antigens, display different toxicity profiles compared with radiolabeled MoAbs. Dose-limiting toxicities may include damage to the liver and myelotoxicity. The drug component is the antimitotic agent auristatin, which is 100-1000 times more potent than doxorubicin. Consequently, auristatin antibody-drug conjugates require a high selectivity in tumor targeting to display pronounced activity at well-tolerated doses. We have evaluated the possibility of increasing the therapeutic index of BR96-auristatin by combining the administration of conjugates with subsequent extracorporeal affinity adsorption treatment.
Rats were injected with biotinylated, monomethyl auristatin F (MMAF)-conjugated monoclonal antibody BR96. The conjugate was then removed from the circulation by extracorporeal affinity adsorption treatment, 24 hours postinjection using an avidin affinity column. By analyzing blood parameters for 100 days, myelotoxicity, hepatotoxicity, and nephrotoxicity were assessed. Body weight, general status, and tumor size were also recorded. The toxicity-reducing effect of extracorporeal affinity adsorption treatment was evaluated.
Extracorporeal affinity adsorption treatment removed 85%-90% of BR96-MMAF from the circulation. Early toxicity-related death was seen in nontumor-bearing animals that were given MMAF-conjugated BR96, in contrast to animals that were given a higher amount of BR96-MMAF with subsequent extracorporeal affinity adsorption treatment, in which all survived 100 days postinjection. Extracorporeal affinity adsorption treatment reduced the loss of body weight, myelotoxicity, and hepatotoxicity.
Extracorporeal affinity adsorption treatment can be used to reduce the toxicity associated with administration of BR96-MMAF conjugates, making it possible to increase the amount of conjugates administered. The combined treatment will be further optimized in future studies. Cancer 2010;116(4 suppl):1033–42. © 2010 American Cancer Society.