Rapamycin nanoparticles increase the therapeutic window of engineered interleukin-2 and drive expansion of antigen-specific regulatory T cells for protection against autoimmune disease

Takashi Kei Kishimoto; Max Fournier; Alicia Michaud; Gina Rizzo; Christopher Roy; Teresa Capela; Natasha Nukolova; Ning Li; Liam Doyle; Fen-Ni Fu; Derek VanDyke; Peter G Traber; Jamie B Spangler; Sheldon S Leung; Petr O Ilyinskii

doi:10.1016/j.jaut.2023.103125

Rapamycin nanoparticles increase the therapeutic window of engineered interleukin-2 and drive expansion of antigen-specific regulatory T cells for protection against autoimmune disease

J Autoimmun. 2023 Oct 14:140:103125. doi: 10.1016/j.jaut.2023.103125. Online ahead of print.

Authors

Affiliations

¹ Selecta Biosciences, Watertown, MA, 02472, USA. Electronic address: kkishimoto@selectabio.com.
² Selecta Biosciences, Watertown, MA, 02472, USA.
³ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA.
⁴ Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA; Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA.

PMID: 37844543
DOI: 10.1016/j.jaut.2023.103125

Abstract

Interleukin-2 (IL-2) therapies targeting the high affinity IL-2 receptor expressed on regulatory T cells (Tregs) have shown promising therapeutic benefit in autoimmune diseases through nonselective expansion of pre-existing Treg populations, but are potentially limited by the inability to induce antigen-specific Tregs, as well as by dose-limiting activation of effector immune cells in settings of inflammation. We recently developed biodegradable nanoparticles encapsulating rapamycin, called ImmTOR, which induce selective immune tolerance to co-administered antigens but do not increase total Treg numbers. Here we demonstrate that the combination of ImmTOR and an engineered Treg-selective IL-2 variant (termed IL-2 mutein) increases the number and durability of total Tregs, as well as inducing a profound synergistic increase in antigen-specific Tregs when combined with a target antigen. We demonstrate that the combination of ImmTOR and an IL-2 mutein leads to durable inhibition of antibody responses to co-administered AAV gene therapy capsid, even at sub-optimal doses of ImmTOR, and provides protection in autoimmune models of type 1 diabetes and primary biliary cholangitis. Importantly, ImmTOR also increases the therapeutic window of engineered IL-2 molecules by mitigating effector immune cell expansion and preventing exacerbation of disease in a model of graft-versus-host-disease. At the same time, IL-2 mutein shows potential for dose-sparing of ImmTOR. Overall, these results establish that the combination of ImmTOR and an IL-2 mutein show synergistic benefit on both safety and efficacy to provide durable antigen-specific immune tolerance to mitigate drug immunogenicity and to treat autoimmune diseases.

Keywords: Adeno-associated virus; Antigen-specific immune tolerance; Autoimmune disease; ImmTOR; Interleukin-2; Primary biliary cholangitis; Rapamycin; Regulatory T cells; Type 1 diabetes.