Preclinical Development of a T Cell Receptor-engineered Regulatory T Cell Therapy for Progressive MS
Jefte Drijvers1, Devan Moodley1, Amina Abbadi1, Eugene Antipov1, Juliana Barrios1, Jeremy Burns1, Katie Callow1, Bethan Chilton1, Yuan Feng1, Michelle Fleury1, Stefan Herrera1, CJ Ives1, Matthias John1, Enoch Kisubika1, Joshua Lengieza1, Geetha Mylvaganam1, Conor O'Malley1, Elissa Murphy1, Timothy Nelson1, Joanna Pizzo1, Lawrence Schweitzer1, Alec Silverman1, Christina Strange1, Grace Voorhees1, Sarah Voytek1, Yizhou Wang1, Stephanie Woodall1, Fang Xia1, Yanbo Zhang1, Richard Zhou1, Jiang Zhu1, Niranjana Nagarajan1, Stephen Sofen1, Andrea van Elsas2, Richard Ransohoff2, Ellen Cahir-McFarland1
1Abata Therapeutics, 2Third Rock Ventures
Objective:
To develop a regulatory T cell (Treg)-based therapy for the treatment of progressive multiple sclerosis (MS).
Background:
Disease-modifying therapies have revolutionized care for relapsing-remitting MS, largely by preventing the influx of peripheral immune cells into the central nervous system (CNS). However, progressive MS is driven by chronic CNS-compartmentalized processes for which no effective therapies exist. Meningeal aggregates play an essential role in this pathology by supporting chronic-active lesions in the CNS parenchyma. Tregs, given their intrinsic ability to suppress immune-mediated inflammation through diverse mechanisms and their phenotypic stability are well-suited to address this aspect of MS pathophysiology. We hypothesize that CNS-targeted Tregs will disrupt meningeal aggregates.
Design/Methods:
A TCR-engineered Treg product was designed to target the CNS antigen myelin basic protein (MBP) in the context of HLA-DRB1*15:01. Candidate T cell receptors (TCRs) were screened through a pipeline of assays for their MBP-reactivity and ability to induce suppressive activity in human Tregs. The best-performing TCR was introduced into Tregs isolated from healthy donor and MS patient leukopaks. The suppressive activity, phenotypic stability, and manufacturability of TCR-engineered Tregs from healthy donor and MS patient materials were characterized.
Results:
The selected MBP-specific TCR induced activation, suppressive activity towards conventional T cells, and suppressive cytokine expression in primary Tregs upon exposure to MBP peptide and antigen-presenting cells. A highly pure Treg product could be manufactured from both healthy donor and MS patient leukopaks as measured by flow cytometry and Treg-specific demethylated region (TSDR) demethylation assays. The functional stability of the Treg cell product was verified throughout the manufacturing process as well as upon activation and exposure to inflammatory cytokines.
Conclusions:
TCR-engineered Tregs display suppressive activity upon exposure to MBP peptide and can be manufactured at high purity for both healthy donors and MS patients. This Treg product is phenotypically stable under inflammatory conditions.