W114 - Nonclinical Toxicology and Safety Studies of MTX-101, an Inhibitory KIR2DL X CD8 Targeting Bispecific CD8 Treg Modulator, Enabling Clinical Development as Therapeutic for the Treatment of Autoimmune Disease

Minh Pham – Mozart Therapeutics; Daniel Boster – Mozart Therapeutics; Phoenicia Quach – Mozart Therapeutics; Gleda Harmansky – Mozart Therapeutics; Lisa Bogatzki – Mozart Therapeutics; Jennifer Gardell – Mozart Therapeutics; Susan Julien – Mozart Therapeutics; Courtney Crane – Mozart Therapeutics; Kristine Swiderek – Mozart Therapeutics

Abstract Text: In healthy individuals, CD8 Treg selectively kill self-reactive CD4 T cells. In autoimmune disease, CD8 Treg appear dysfunctional and insufficient to eliminate self-reactive CD4 T cells, in part due to expression of the autoimmune checkpoint KIR2DL. MTX-101 is designed to target and selectively activate only CD8 Treg to restore immune balance, reduce inflammation, pro-inflammatory cytokines and disease pathology.

MTX-101, at repeat doses up to 100mg/kg, was evaluated in a GLP toxicology study using a humanized CD34+-engrafted NSG(IL-15Tg) mouse model. In-life safety, during dosing and recovery, and terminal evaluations demonstrated that MTX-101 was well-tolerated with no drug-related findings observed. While high levels of target expressing cell binding was seen, no changes of immune cell frequency or activation status were noted. No cytokine release was detected. High exposure over course of study was observed with PK consistent to PK in normal Balb/c mice and cynomolgus monkeys.

MTX-101 was evaluated for cytokine release in human whole blood or PBMC (multiple assay formats), with no elevation of cytokine detected. In vitro immunogenicity evaluation suggests low risk of ADA, consistent with a lack of impact to PK of MTX-101 in vivo. MTX-101 was assessed for off-target binding via the Retrogenix protein library microarray platform. No strong binding was observed other than expected interactions to its KIR2DL and CD8 targets.

In conclusion, nonclinical safety studies support clinical entry into a Ph1a/b healthy adult and patient study. MTX-101 is a promising therapeutic approach to address an underlying cause of autoimmune disease via enhancement of CD8 Treg function.