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Executive Summary

FDA MONOCLONAL ANTIBODY IMMUNE RESPONSE ASSAY STANDARD could assist IND sponsors conducting in vivo studies, Hybritech investigator Barbara Unger, PhD, suggested at an FDA sponsored workshop held Sept. 26-27. The agency could consider providing "a panel or a grouping of positive sera along with a monoclonal antibody that it's reactive with," Unger said. "Maybe this can be provided at cost to those individuals who hold federally approved INDs." The subject of an assay standard was raised after several presentations on the incidence of human antimurine antibody (HAMA) response to murine monoclonal antibodies. Investigators are interested in determining the amount of HAMA response induced by murine monoclonal antibodies because such a response can interfere with the efficacy of the monoclonals. The HAMA response could be a "rate limiting step" for the development of murine monoclonal antibody products, Elaine Esber, MD, associate director for research and regulatory coordination, FDA Center for Biologics Evaluation and Research, noted. FDA Division of Biological Investigational New Drugs medical officer Curtis Scribner, MD also addressed the need "to standardize" an assay for HAMA. "Clearly HAMA alters the biodistribution and the kinetics of many of these antibodies," Scribner remarked. In addition to the standard assay, Scribner suggested that industry consider the use of skin tests to determine reactivity before injection of the antibody, as well as "classification of immune response," to gain an understanding of the "underlying mechanism" of HAMA. Scribner co-chaired the symposium. Among those echoing Scribner's proposals was Center for Molecular Medicine and Immunology (CMMI) Clinical Director Joan Horowitz, MD, who asked that clinicians try to "categorize the reaction that our patients have, based on standard immunology of the type I, type II, type III, type IV response, so that we can have a better universal language and better compared results from our human trials." Emphasizing the "importance of the skin test," Horowitz presented Phase I/II studies in 66 patients showing that of nine testing positive in skin tests for HAMA, seven had "systemic symptoms during the infusion or immediately following the infusion" of anticarcinoembryonic antigen (CEA) monoclonal antibodies. Some workshop participants, while agreeing to a need for standardization, discounted the effectiveness of skin tests to predict allergic reaction. "It would be convenient," Xoma President Patrick Scannon, MD, said, "if we had a standard assay format that could be agreed upon for comparison of results." However, he continued, "we think that skin tests have no value in predicting allergic reactions." Scannon pointed out that a Xoma study with the monoclonal XomaZymeMel showed that 10% of patients with positive skin tests had allergic reactions to the drug vs. 7% of patients who tested negative. Other effects of HAMA were demonstrated in transplant rejection studies conducted by Roy First, MD, University of Cincinnati. According to First, failure of reversal of transplant rejections was associated with high HAMA titers. "It is absolutely essential that immune monitoring is carried out during retreatment," First advised. "In patients with high titer antimurine antibodies, we feel that OKT3 should not be used." The proceedings of the symposium are scheduled to be published in about two months under the title, "The Significance of the Human Resource to Monoclonal Antibodies." The book will be available to conference participants for $ 35-40 and on the commercial market for $ 45-50. Copies may be obtained from FDA Division of Biological Investigational New Drugs.

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