Mitigation of Anti-drug Antibodies (ADAs) against a Pegylated Uricase in Patients with Hyperuricemia Results in Enhanced Control of Serum Uric Acid
Earl Sands1, Alan J. Kivitz2, Lloyd Johnston1, Takashi Kei Kishimoto1, 1Selecta Biosciences, Watertown, MA; 2Altoona Center for Clinical Research, Altoona, PA
The development of ADAs is a common cause of treatment failure and hypersensitivity reactions. We have demonstrated that synthetic vaccine particles encapsulating rapamycin (SVP-R), are capable of inducing durable immunological tolerance to biologics, resulting in improved efficacy in disease relevant animal models (Kishimoto et al., Nature Nanotech 2016). Here, we report on our translation of these findings to humans by demonstrating the addition of SVP-R to pegsiticase, a pegylated uricase enzyme, mitigated the formation of ADAs, enabling sustained control of serum uric acid levels for at least 30 days after a single dose in patients with hyperuricemia in a Phase 1 open-label multicenter clinical trial. Patients with sUA >6 mg/dl dosed with pegsiticase alone showed an immediate drop in sUA, which returned to baseline levels by 14-21 days in 4 of 5 subjects, correlating with the induction of anti-uricase antibody titers >1000. Patients treated with SVP-R alone showed no meaningful change in sUA. Those treated with SEL-212, the combination of SVP-R and pegisiticase, showed a dose-dependent inhibition of anti-uricase ADAs and corresponding decrease in sUA levels through at least day 30 after a single injection. There was a strong correlation between maintenance of low uric acid levels and low or no ADA titers. These results support monthly dosing in an ongoing Phase 2 multi-dose study in symptomatic gout patients and the potential use of SVP-R to mitigate ADAs for other immunogenic biologics.
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