W125 - Pre-clinical Pharmacologic and Tolerability Characterization of MTX-101, a Novel kirxcd8 Targeting Bispecific CD8 Treg Modulator

Daniel Boster; Monica Childs; Courtney Crane; Rachael Fasnacht; Kristin Fitzpatrick; Jennifer Gardell; Susan Julien; Minh Pham; Kristine Swiderek; Cong Tan

Abstract Text: In healthy individuals, CD8 Treg activation leads to selective elimination of self-reactive CD4 T cells. The CD8 Treg network appears dysfunctional in autoimmune diseases and insufficient to kill self-reactive CD4 T cells, in part due to expression of inhibitory KIR2DL1/2/3; We have developed MTX-101, a bispecific CD8 Treg modulator targeting CD8 and KIR2DL(1/2/3) molecules. MTX-101 targets CD8 Treg, activating the cells, thereby reducing inflammation without increasing unwanted immune cell activation or pro-inflammatory cytokines. Our early data suggest that MTX-101-mediated enhancement of CD8 Treg function is a broadly applicable and a promising CD8 Treg specific therapeutic to restore immune balance for the treatment of autoimmune diseases, including gastrointestinal indications (eg., celiac disease, Crohn’s and ulcerative colitis).

We have evaluated the binding and specificity profiles of MTX-101 in vitro and in vivo, . No activation of immune cells or increased proinflammatory cytokines were observed in vitro and improved outcomes were demonstrated in an acute inflammatory GVHD model. In both Balb/c and in humanized CD34+-engrafted NSG(IL-15Tg) mice, the pharmacokinetic profile of MTX-101 was consistent with antibody-like molecules. We evaluated binding, impact to immune cell phenotypes, pharmacology and early tolerability of MTX-101 in humanized mice and observed detectable binding on immune cells in peripheral blood and terminal tissues, with no resulting activation. Importantly, no induction of proinflammatory cytokines in the serum was observed following a single dose of MTX-101. Evaluation of PK/PD and biomarker readouts in this model will inform clinical dosing and development of MTX-101 to improve treatment outcomes in autoimmune disease patients.