OP0002 IMMTOR NANOPARTICLES ENHANCE THE TOLEROGENIC ENVIRONMENT OF THE LIVER IN MICE

Background: Tolerogenic ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to mitigate the formation of anti-drug antibodies against pegadricase, a pegylated uricase enzyme, which enabled monthly dosing and sustained reduction of serum uric acid levels in a Phase 2 clinical trial of SEL-212, a combination of pegadricase + ImmTOR, in patients with symptomatic gout with hyperuricemia. Prior mechanism of action studies showed selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration in mice. In the spleen, ImmTOR has been demonstrated to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomized mice showed a partial but incomplete abrogation of the tolerogenic immune response mediated by ImmTOR. Objectives: Here we evaluated the ability of ImmTOR to enhance the tolerogenic environment in the liver. Results: All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4+ and CD8+ T cells, and the emergence of a large population of CD4–CD8– (double negative) T cell population. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. Conclusion: These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR in mitigating anti-drug antibody responses to biologic therapies, such as pegadricase. Disclosure of Interests: Petr Ilyinskii Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Christopher Roy Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Julie LePrevost Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences, Kei Kishimoto Shareholder of: Selecta Biosciences, Employee of: Selecta Biosciences