Pre-clinical pharmacologic and tolerability characterization of a novel KIRxCD8 targeting bispecific CD8 Treg modulator

Abstract

Abstract We have characterized a subset of CD8 T cells (CD8 Treg) with immunosuppressive characteristics in inflammatory disease settings. Here we describe the binding and specificity profiles of a novel bispecific CD8 Treg modulator in vitro, ex vivo, and in vivo, and initial assessment of tolerability and pharmacology in a humanized mouse model. We evaluated the binding, pharmacokinetics (PK), and early tolerability of the bispecific CD8 Treg modulator targeting CD8 and KIR2DL1/2/3. Despite single arm binding to NK cells via the KIR targeting arm and CD8 T cells by the CD8 targeting arm of the bispecific, we did not detect activation of immune cells or increased pro-inflammatory cytokines in vitro, nor did we observe any contribution of NK cells to the elimination of pathogenic CD4 T cells. In healthy mice, the CD8 Treg modulator had a PK profile consistent with antibody molecules; treatment delayed disease onset in an acute GVHD setting. In humanized CD34-engrafted NSG-IL-15 transgenic mice, supporting engraftment of NK cells, no activation of immune cells in peripheral blood or terminal tissues or induction of proinflammatory cytokines in the serum was observed following a single dose of the CD8 Treg modulator. The recently described CD8 Treg network appears dysfunctional in autoimmune diseases. The KIRxCD8 targeting bispecific modulator targets this network, engages and activates CD8 Treg and reduces inflammation without increasing unwanted immune cell activation or pro-inflammatory cytokines, both in vitro and in vivo. Our early data suggest that KIR-mediated enhancement of CD8 Treg function using a bispecific modulator is a broadly applicable and a promising CD8 Treg specific therapeutic modality for the treatment of autoimmune disease.