(Curis) Preclinical evaluation of anti-VISTA antibody CI-8993 in a syngeneic huVISTA-KI model

Introduction

VISTA [V-domain immunoglobulin (Ig) suppressor of T cell activation] is a type 1 transmembrane protein and member of the PD-1/PD-L1 family of the Ig superfamily. VISTA is expressed in the hematopoietic compartment including on circulating and intratumoral myeloid cells. Within the T lymphocyte compartment, VISTA is most highly expressed on naïve CD4+ and Foxp3+ regulatory T cells [1]. Moreover, tumor types, particularly lung cancer, show VISTA expression primarily in the stromal myeloid infiltrate [2-4].

VISTA acts as a co-inhibitory receptor of resting CD4+ T cells that negatively regulate T cell activation in vitro; and therefore, plays a critical role in enforcing quiescence (inactivity or dormancy) and inhibits anti-tumor immune responses [1].

The Investigational Product CI-8993 is a fully human IgG1κ monoclonal antibody that binds specifically to this immune checkpoint molecule. Phase I safety has been investigated in a prior trials in patients with advanced cancer (NCT02671955) and continues to be explored in Curis’ NCT04475523 study. To assist determining the pharmacokinetics and biodistribution of CI-8993 in patients we aimed to develop Zirconium-89 (⁸⁹Zr)-labeled CI-8993 for PET imaging and quantitation, and validate in preclinical models prior to a planned human trial.