Nonclinical Safety Assessment of SBT777101, a CAR-Engineered Regulatory T Cell Therapy for Autoimmune Diseases.

Authors

Herve Lebrec, Jonathan M Clingan, Anne-Renee van der Vuurst de Vries, Lauren Mihalcik, Yuchi Honaker, Sara Charmsaz, Seonhwa Dura, Kathryn Hooper, Yuanyuan Xiao, Michelle Blake, Max Fiebiger, Radha Dhayal, Christine Saechao, Alexandre Iannello, Fred Ramsdell, Jeffrey A Bluestone, Josh Beilke

Published in

Toxicological sciences : an official journal of the Society of Toxicology. Sep 15, 2026. Epub Sep 15, 2026.

Abstract

Chimeric antigen receptor (CAR)-regulatory T cell (Treg) therapies represent a promising approach for autoimmune diseases, but their nonclinical safety assessment remains challenging due to antigen-, disease-, and species-specific pharmacology that limits the relevance of conventional animal models. SBT777101, a CAR-Treg therapy targeting citrullinated proteins associated with rheumatoid arthritis and hidradenitis suppurativa, was evaluated using a nonclinical strategy centered on in vitro and ex vivo New Approach Methodologies (NAMs) and in vivo studies benchmarked against untransduced polyclonal Tregs which are manufactured identically but lack the CAR and have an established clinical safety record, complemented by immunodeficient mouse studies. We hypothesized that CAR engineering would not destabilize the Treg phenotype or introduce new toxicological liabilities relative to polyclonal Tregs. SBT777101 maintained phenotypic stability under repeated stimulation and pro-inflammatory conditions, produced minimal pro-inflammatory cytokines following activation, and demonstrated immunomodulatory activity comparable to untransduced Tregs. Tissue cross-reactivity and primary cell studies identified limited membrane-associated binding, no evidence of CAR-mediated cytotoxicity or activation in normal human tissues, and no off-target binding by broad protein array screening. Immunosuppressive activity toward natural killer and CD8+ T cell responses was limited and comparable to polyclonal Tregs. Lentiviral integration site analyses demonstrated polyclonal integration profiles without evidence of transformation or abnormal growth in a cytokine- and activation-independent growth assay. This study establishes a combination of in vivo and NAM-based nonclinical safety framework for CAR-Treg therapies and demonstrates that CAR engineering of SBT777101 does not introduce new safety liabilities relative to unmodified polyclonal Tregs. These findings supported progression of SBT777101 into Phase 1 clinical trials and offer a generalizable approach for evaluating the safety of future CAR-Treg therapeutics.

PMID:
42745475
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.