Pre-clinical Pharmacology and Tolerability Characterization of a Novel KIRxICOS Targeting Bispecific CD8 Treg Modulator

Abstract Here we present an Fc-based bispecific CD8 Treg modulator that binds in cis to inhibitory KIR and ICOS receptors co-expressed by CD8 Treg designed to restore CD8 Treg functions. CD8 Treg dysfunctions include impaired cytotoxicity and insufficient longevity in autoimmune disease affected tissues. The KIRxICOS targeting bispecific molecule selectively enhances CD8 Treg killing, promoting their recruitment to and survival within disease affected tissues. Through in vitro, ex vivo, and in vivo evaluations in humanized mouse models, we assessed binding, specificity, and function of the KIRxICOS CD8 Treg Modulator, which boosted ICOS signaling in KIR-expressing CD8 Treg, without activating immune cells expressing only ICOS. It extended survival and reduced disease score in a humanized acute GvHD model, marked by a reduction of activated CD4 T cells and an increase of CD8 Treg. In antigen stimulated tissues, the KIRxICOS CD8 Treg modulator reduced CD4 derived proinflammatory cytokines and epithelial cell death. In vivo, the KIRxICOS molecule demonstrated antibody-like PK parameters. Repeat dose studies in huNSG(IL15Tg) mice indicated good tolerability without terminal toxicity or induction of proinflammatory serum cytokines. The evaluation of binding, impact on immune cell phenotypes, and pharmacology revealed immune cell binding without activation. Our preclinical data supports development of the KIRxICOS CD8 Treg modulator as a therapeutic in autoimmune disease.