Tolerogenic nanoparticles mitigate the formation of anti-drug antibodies against pegylated uricase in patients with hyperuricemia

Abstract

Biologic drugs have transformed the standard of care for many diseases. However, many biologics induce the formation of anti-drug antibodies (ADAs), which can compromise their safety and efficacy. Preclinical studies demonstrate that biodegradable nanoparticles-encapsulating rapamycin (ImmTOR), but not free rapamycin, mitigate the immunogenicity of co-administered biologic drugs. Here we report the outcomes from two clinical trials for ImmTOR. In the first ascending dose, open-label study (NCT02464605), pegadricase, an immunogenic, pegylated uricase enzyme derived from Candida utilis, is assessed for safety and tolerability (primary endpoint) as well as activity and immunogenicity (secondary endpoint); in the second single ascending dose Phase 1b trial (NCT02648269) composed of both a double-blind and open-label parts, we evaluate the safety of ImmTOR (primary endpoint) and its ability to prevent the formation of anti-drug antibodies against pegadricase and enhance its pharmacodynamic activity (secondary endpoint) in patients with hyperuricemia. The combination of ImmTOR and pegadricase is well tolerated. ImmTOR inhibits the development of uricase-specific ADAs in a dose-dependent manner, thus enabling sustained enzyme activity and reduction in serum uric acid levels. ImmTOR may thus represent a feasible approach for preventing the formation of ADAs to a broad range of immunogenic biologic therapies.

Conflict of interest statement

E.S., W.D., S.S.L., L.J., and T.K.K are current or former employees and shareholders of Selecta Biosciences.

© 2022. The Author(s).

Figures

Fig. 1. Schematic of ImmTOR mechanism of action. ImmTOR is selectively taken up by antigen-presenting cells, such as dendritic cells (DC) in the spleen and liver.

ImmTOR induces tolerogenic DCs that process and present co-administered antigen in a manner that results in the expansion of antigen-specific regulatory T cells. The Tregs inhibit activation of effector T cells and prevent the formation of anti-drug antibodies. Adapted from Kishimoto.

Fig. 2. Single ascending dose study of pegadricase in patients with hyperuricemia.

A Patients with sUA > 6 mg/dL at screening were assigned to one of five cohorts receiving a single IV infusion of pegadricase (0.1, 0.2, 0.4, 0.8 or 1.2 mg/kg). Each cohort consisted of 5 patients, except for cohort 5 (1.2 mg/kg) which enrolled 2 patients. Blood was drawn at various timepoints indicated and sUA levels were determined. Lines represent the mean for each cohort and error bars represent the standard deviation. Only the mean is depicted for cohort 5. B Serum uric acid, serum pegadricase activity, and anti-uricase IgG antibodies are shown for the five individual patients in cohort 3 (0.4 mg/kg pegadricase). One patient (square symbols) developed only low anti-uricase IgG titers and showed prolonged reduction of sUA and sustained serum pegadricase activity. Source data are provided as a Source Data file.

Fig. 3. Single ascending dose study of ImmTOR and SEL-212 in patients with hyperuricemia.

A Schematic of cohorts dosed with pegadricase alone (Cohort A), single escalating doses of ImmTOR alone (Cohorts B–E), or single escalating doses of SEL-212 (Cohorts F–J, 0.03, 0.1, 0.15, or 0.3 mg/kg ImmTOR combined with a fixed dose of 0.4 mg/kg pegadricase). Cohorts B–E were double blinded and randomized to either placebo or study drug in a 2:5 rato, while Cohorts A and F–J were open-label. All cohorts consisted of 5 drug-treated patients, except for Cohort G, that contained 10 patients and Cohort J which contained 6 patients. In addition, Cohorts B–F each contained two patients that received placebo (vehicle). Patients in Cohorts F–I received an IV infusion of ImmTOR followed immediately by an IV infusion of pegadricase. Patients in Cohort J received an IV infusion of pegadricase followed 48 h later by an IV infusion of ImmTOR. B Serum uric acid levels over time. Each symbol represents sUA levels for an individual patient at various timepoints indicated and the lines indicate mean sUA levels for the cohort. The dotted black line represents 6 mg/dL sUA. Source data are provided as a Source Data file.

Fig. 4. Correlation of sUA with anti-uricase IgG and serum pegadricase activity.

Anti-uricase IgG titers, serum pegadricase activity, and sUA are plotted against time for individual patients in cohorts A, G, H, and I. Each line represents an individual patient.

Fig. 5. Serum uric acid and anti-uricase IgG for selected patients followed past day 30.

Patients in cohorts G, H, and I that maintained sUA levels below 6 mg/dL for 30 days were selected on a voluntary basis to participate in additional monitoring. Serum uric acid and anti-uricase IgG titers are plotted for individual patients at various timepoints indicated. Patients in cohorts G, H, and I are represented by circle, square, and triangle symbols, respectively. All patients showed a rebound in sUA levels by day 50, indicating clearance of enzyme. Ten of the twelve patients showed no increase in anti-uricase IgG titers after day 30 and the remaining two patients showed only modest elevations in anti-uricase IgG titers. Source data are provided as a Source Data file.