Abstract 4508: Modulating the release rate of polyethylene glycol (PEG) polymers from interleukin-2 (IL-2) PEG conjugates to optimize anti-tumor efficacy

Abstract

Abstract The cytokine interleukin-2 (IL-2) is an endogenous agonist of the IL-2 pathway that activates and expands tumor killing lymphocytes. High doses of IL-2 are needed to activate CD8 T cells and NK cells, through binding on low-affinity IL-2 receptor beta gamma subunits (IL-2Rβγ). Severe toxic side effects associated with high doses, as well as the poor PK profile of IL-2, have limited its clinical usage. In addition of the toxicities, IL-2 also stimulates proliferation and activation of regulatory T cells (Tregs) through binding on the high-affinity heterotrimeric IL-2 receptor alpha beta gamma subunits (IL-2Rαβγ), which may antagonize the intended anti-tumor immunity. We report on an IL-2 PEGylation strategy to improve the pharmacokinetic properties of IL-2. Utilizing our proprietary PEGylation technology, IL-2 was covalently connected with multiple polyethylene glycol (PEG) polymers through releasable linkers. Our technology enabled the conjugation of IL-2 with average of 5-6 polyethylene glycol (PEG) polymers in high efficiency and 80-90% isolated yield. Anti-tumor efficacy of IL-2 was optimized by modulating the hydrolysis rate of the releasable linkers connecting IL-2 and polymers. The releasable linkers used in the study had the hydrolysis rate in the range of 15 to 120 hours to release one PEG polymer from the conjugates. The conjugates with hydrolysis rate of 20-60 h showed the optimal anti-tumor efficacy in B16F10 animal model. These results suggest that our novel approach of IL-2 PEGylation may optimize IL-2 biological activity and anti-tumor efficacy. Modulating the releasable rate of the PEG polymer would optimize the pharmacokinetic properties of the released active IL-2 species and enable the optimized anti-tumor efficacy. We are currently exploring the usage of our technology platform to further engineer IL-2 as a non-IL2Rα binding conjugate for improved toxicity profile. Citation Format: Hui Li, Yuntao Song, Haiping Zhou, Chuan Liao, Meng Xu, Chuang Li. Modulating the release rate of polyethylene glycol (PEG) polymers from interleukin-2 (IL-2) PEG conjugates to optimize anti-tumor efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4508.