97-OR: Preclinical Characterization of MTX-101, a Novel KIRxCD8 Targeting Bispecific CD8 Treg Modulator

Introduction and Objectives: In healthy individuals, activation and expansion of CD8 regulatory T cells (CD8 Treg) leads to selective killing of pathogenic CD4 T cells without broad immunosuppression. In patients with autoimmunity, CD8 Treg appear dysfunctional, allowing pathogenic CD4 T cell expansion and downstream inflammatory events, causing damage to healthy tissues. MTX-101 is a bispecific CD8 Treg modulator targeting CD8 and KIR2DL(1/2/3), co-expressed on CD8 Treg. MTX-101 targets CD8 Treg to restore their function and reduce inflammation without unwanted immune cell activation or global immune suppression. By targeting a root cause of CD4-driven autoimmune diseases, our data suggest that MTX-101 is a promising CD8 Treg-specific therapeutic to restore immune balance for the treatment of Type 1 Diabetes (T1D).

Methods: We evaluated MTX-101 binding, mechanism of action, and specificity in vitro using human PBMCs and in vivo using a human CD4 T cell-driven GVHD model. Pharmacology and early tolerability were evaluated in humanized CD34+-engrafted NSG(IL-15Tg) mice.

Results: MTX-101 increased the activation and functions of CD8 Treg without activating other immune cells or affecting global immune responses in vitro, and improved outcomes in the acute GVHD model. In Balb/c and humanized mice, MTX-101 pharmacokinetics were consistent with antibody-like molecules. In humanized mice, MTX-101 bound CD8 Treg in peripheral blood and terminal tissues, with no resulting activation of immune cells. No induction of proinflammatory serum cytokines were observed following MTX-101 dosing at concentrations up to 50 mg/kg.

Conclusion: MTX-101 restores CD8 Treg functions and may provide durable resistance to autoimmune disease progression.