Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Initiation of urate-lowering therapies is typically associated with an increase in gout flares due to mobilization of pro-inflammatory urate crystals. SEL-212 is a novel combination product consisting of pegadricase (also known as pegsiticase), a pegylated uricase, co-administered with synthetic vaccine particles encapsulating rapamycin (SVP-R) being developed for the treatment of chronic severe gout. Data from the ongoing open-label Phase 2 multidose study of SEL-212 indicate that SVP-R mitigates the formation of anti-drug antibodies (ADAs) against pegadricase, enabling monthly dosing and sustained control of serum uric acid (sUA) levels in most patients. Despite rapid and sustained reduction of sUA, patients treated with SEL-212 experienced a low rate of flares. Here we evaluated in animal studies whether SVP-R might have a beneficial effect on reducing inflammation induced by monosodium urate crystals (MSU) in addition to its effects on mitigating the formation of ADAs.
Methods: MSU-induced inflammation was investigated in an air pouch model in C57Bl/6 mice. An air pouch was generated on the dorsal aspect of a mouse by injecting sterile air on d0 and d3. Mice were treated intravenously with placebo or SVP-R on d7. MSU crystals were injected in the air pouch on d8 and mice were sacrificed 5 hours after MSU injection. Air pouch exudate was analyzed for cellularity and interleukin-1β (IL-1β) levels as markers of inflammation.
Results: Injection of MSU crystals into the air pouch of a mouse has been previously shown to induce an acute inflammatory response characterized by expression of IL-1β and an influx of neutrophils. Intravenous administration of SVP-Rapamycin reduced the generation of IL-1β in the air pouch exudate by four-fold (from 131.5 pg/ml to 30.5 pg/ml) and the number of Ly6G+CD11b+ neutrophils by five-fold (from 0.5×106 cells/ml to 0.1×106 cells/ml).
Conclusion: SVP-R has been shown to mitigate the formation of ADAs to biologic therapies by inducing tolerogenic dendritic cells and antigen-specific regulatory T cells. Here we demonstrate that SVP-R also attenuates inflammatory responses induced by MSU crystals and mediated by innate immune cells. These results may explain why gout patients treated with pegadricase in combination with SVP-R experience an unexpectedly low rate of gout flares.
To cite this abstract in AMA style:Kolte P, LaMothe R, Ferrari J, Leung S, DeHaan Ph.D. W, Sands E, Kishimoto TK. Mitigation of Inflammation Induced By Monosodium Urate Crystals in Mice By Treatment with Svp-Rapamycin [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/mitigation-of-inflammation-induced-by-monosodium-urate-crystals-in-mice-by-treatment-with-svp-rapamycin/. Accessed August 24, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mitigation-of-inflammation-induced-by-monosodium-urate-crystals-in-mice-by-treatment-with-svp-rapamycin/