Abstract Details

Title Preclinical Development of a T Cell Receptor-engineered Regulatory T Cell Therapy for Progressive MS

Topic Multiple Sclerosis

Presentation(s) S17 - Multiple Sclerosis: Immunology/Basic Sciences (1:36 PM-1:48 PM)

Poster/Presentation
Number 004

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.

Objective To develop a regulatory T cell (Treg)-based therapy for the treatment of progressive multiple sclerosis (MS).

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.

Authors/Disclosures
Jefte Drijvers (Abata Therapeutics) PRESENTER	No disclosure on file
Devan Moodley (Abata Therapeutics)	No disclosure on file
Amina Abbadi (Abata Therapeutics)	No disclosure on file
Eugene Antipov (Abata)	No disclosure on file
Juliana Barrios (Abata Therapeutics)	No disclosure on file
Jeremy Burns	No disclosure on file
Katie Callow	No disclosure on file
Bethan Chilton (Abata Therapeutics)	No disclosure on file
Yuan Feng (Abata Therapeutics)	No disclosure on file
Michelle Fleury (Abata Therapeutics)	No disclosure on file
Stefan Herrera (Abata Therapeutics)	No disclosure on file
CJ Ives (Abata Therapeutics)	No disclosure on file
Matthias John (Abata Therapeutics)	No disclosure on file
Enoch Kisubika (Abata Therapeutics)	No disclosure on file
Joshua Lengieza (Abata Therapeutics)	No disclosure on file
Geetha Mylvaganam (Abata Therapeutics)	No disclosure on file
Conor O'Malley	No disclosure on file
Elissa Murphy (Abata Therapeutics)	No disclosure on file
Timothy Nelson (Abata Therapeutics)	No disclosure on file
Joanna Pizzo (Abata Therapeutics)	No disclosure on file
Larry Schweitzer	No disclosure on file
	No disclosure on file
Christina Strange (Abata Therapeutics)	No disclosure on file
Grace Voorhees (Abata Therapeutics)	No disclosure on file
	No disclosure on file
Yizhou Wang (Abata Therapeutics)	No disclosure on file
Stephanie Woodall (Abata Therapeutics)	No disclosure on file
Fang Xia (Abata Therapeutics)	No disclosure on file
Yanbo Zhang (Abata Therapeutics)	No disclosure on file
Richard Zhou	No disclosure on file
Jiang Zhu (Home)	No disclosure on file
Niranjana Nagarajan (Abata Therapeutics)	No disclosure on file
Stephen Sofen (Abata Therapeutics)	No disclosure on file
Andrea Van Elsas (Third Rock Ventures)	No disclosure on file
Richard M. Ransohoff, MD (Third Rock Ventures)	Dr. Ransohoff has received personal compensation for serving as an employee of Third Rock Ventures. Dr. Ransohoff has stock in Biogen. Dr. Ransohoff has received intellectual property interests from a discovery or technology relating to health care.
Ellen Cahir-McFarland (Abata Therapeutics)	No disclosure on file