Methodology to Assess the Disposition of Aß1-40–ponezumab Complexes in a Treated Cynomolgus Monkey
P2-494
Background: Ponezumab (PF-04360365) is a humanized anti-Aß40 monoclonal antibody in clinical development as a potential therapeutic to inhibit disease progression in subjects with mild-to-moderate Alzheimer's disease (AD). The goal of the present study was to evaluate the disposition of radiolabeled Aß1-40 and Aß1-40-ponezumab complexes in bile-duct cannulated cynomolgus monkeys. Methods: Non-human primates (NHP) were administered either an intravenous (IV) bolus of Aß1-40 I125 alone (NHP #1, n=1) or 10 mg/kg of IV ponezumab followed by Aß1-40 I125 (NHP #2, n=1). Plasma Aß1-40 I125 was measured using immunoprecipitation by ponezumab-Protein G for NHP #1, whereas the ponezumab-Aß complexes were precipitated by Protein G for NHP #2. Total radioactivity levels were measured in bile and urine as well as certain selected organs to assess the disposition in both NHP. Results: In NHP #1, plasma Aß I125 was below the lower limit of quantitation (LLOQ) by 4 hours and approximately 80% of Aß I125 radioequivalents were excreted into urine over 24 hours. In NHP #2, plasma Aß I125 did not reach LLOQ until 7 days post dose. Approximately 0.01%, 0.3% and 80% of radioequivalents from the Aß I125 dose were recovered in extracted organs (total from kidney, liver and small intestines), bile and urine, respectively, by 15 days post dose. Conclusions: The method described in this exploratory study allowed for evaluation of the disposition of plasma Aß1-40 I125 and Aß I125 radioequivalents in the presence and absence of ponezumab. This method could be further utilized in more definitive study designs for other anti-Aß biotherapeutic modalities.
Manoj Rajadhyaksha, Pfizer Inc.
Ellen Wang, Pfizer Inc.
Carol Cronenberger, Pfizer Inc.
James Kupiec, Pfizer Inc.
Susan Hurst, Pfizer Inc.
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