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Effects of Peptide-Induced Humoral Responses and Preexisting Antibodies in Nonhuman Primates and HIV-Infected Patients Following Chronic Administration of T-20. B. DIMASSIMO*, D. MILAM, P. RUSNAK, D. HIGGINS, R. SMITH, B. BAKER, A. DUSEK, S. HOPKINS, and T. VENETTA. Trimeris, Inc., Durham, NC The effects of reactive serum antibodies on the pharmacokinetics and efficacy of T-20 were evaluated in two nonclinical studies in cynomolgus monkeys and two clinical studies in which T-20 was administered as either a monotherapy or in combination with other HIV medications. In cynomolgus monkeys, antibody induction was dose-dependent following intravenous administration of T-20 for twenty-eight days. In a nine-month toxicity study in which T-20 was administered subcutaneously at higher doses, nearly all animals developed circulating antibodies reactive with T-20 in ELISA. In both studies, the pharmacokinetics of T-20 did not change over time, indicating that circulating antibodies did not alter systemic clearance of the drug. In clinical trials TRI-003 and T20-205, half of the patients exhibited preexisting anti-gp41 serum antibodies that recognized T-20. During treatment, antibody concentrations decreased in the majority of these patients and remained lower than their respective screening levels for the remainder of the study. Most of the patients that were antibody negative at screening remained undetectable throughout the study. No correlation between the presence of antibodies and significant alterations in T-20 pharmacokinetics was found. Decreases in viral load from baseline were comparable between patients that presented preexisting antibodies and patients that were antibody negative. No correlation between the presence of circulating antibodies and the occurrence of serious adverse events was found. Specific humoral responses to T-20 were elicited in nonhuman primates following repeat administration but not in HIV-positive patients receiving T-20 through 16 weeks. Furthermore, antibodies that are raised against native HIV-1 gp41 and cross-react with T-20 do not affect the pharmacokinetics and efficacy of T-20 in HIV-positive patients and do not appear to cause any serious safety concerns. Key Words: Antiretroviral, Entry, Fusion |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |