Induction of long-term tolerance to a specific antigen using anti-CD3 lipid nanoparticles following gene therapy

Chun-Yu Chen; Amber Vander Kooi; Alex Cavedon; Xiaohe Cai; Jonathan Hoggatt; Paolo G V Martini; Carol H Miao

doi:10.1016/j.omtn.2023.102043

Induction of long-term tolerance to a specific antigen using anti-CD3 lipid nanoparticles following gene therapy

Mol Ther Nucleic Acids. 2023 Oct 5:34:102043. doi: 10.1016/j.omtn.2023.102043. eCollection 2023 Dec 12.

Authors

Chun-Yu Chen¹, Amber Vander Kooi¹, Alex Cavedon², Xiaohe Cai¹, Jonathan Hoggatt², Paolo G V Martini², Carol H Miao^{1

3}

Affiliations

¹ Seattle Children's Research Institute, Seattle, WA 98101, USA.
² Moderna, Inc., Cambridge, MA 02139, USA.
³ Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

Abstract

Development of factor VIII (FVIII) inhibitors is a serious complication in the treatment of hemophilia A (HemA) patients. In clinical trials, anti-CD3 antibody therapy effectively modulates the immune response of allograft rejection or autoimmune diseases without eliciting major adverse effects. In this study, we delivered mRNA-encapsulated lipid nanoparticles (LNPs) encoding therapeutic anti-CD3 antibody (αCD3 LNPs) to overcome the anti-FVIII immune responses in HemA mice. It was found that αCD3 LNPs encoding the single-chain antibodies (Fc-scFv) can efficiently deplete CD3⁺ and CD4⁺ effector T cells, whereas αCD3 LNPs encoding double-chain antibodies cannot. Concomitantly, mice treated with αCD3 (Fc-scFv) LNPs showed an increase in the CD4⁺CD25⁺Foxp3⁺ regulatory T cell percentages, which modulated the anti-FVIII immune responses. All T cells returned to normal levels within 2 months. HemA mice treated with αCD3 LNPs prior to hydrodynamic injection of liver-specific FVIII plasmids achieved persistent FVIII gene expression without formation of FVIII inhibitors. Furthermore, transgene expression was increased and persistent following secondary plasmid challenge, indicating induction of long-term tolerance to FVIII. Moreover, the treated mice maintained their immune competence against other antigens. In conclusion, our study established a potential new strategy to induce long-term antigen-specific tolerance using an αCD3 LNP formulation.

Keywords: MT: Delivery Strategies; anti-CD3 antibody; factor VIII; gene transfer; hemophilia A; immune modulation; inhibitory antibody; lipid nanoparticle; mRNA delivery; nonviral.

Abstract

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