（Sensei）腫瘍微小環境におけるVISTAに対して高い選択性を示すモノクローナル抗体であるSNS-101は、良好な薬物動態およびサイトカイン放出特性を示し、抗PD-1療法の反応性を増強する

はじめに

VISTA (V-domain Ig suppressor of T-cell activation) is an immune checkpoint, which suppresses T-cell activation and is highly expressed on myeloid cells, including macrophages and neutrophils¹. Importantly, VISTA is only active at low pH (~pH 6) such as in the tumor microenvironment (TME) due to protonation of surface exposed histidine residues². VISTA inhibition demonstrated excellent therapeutic potential in preclinical studies³. However, clinical development of anti-VISTA antibodies has been challenging due to three major factors: 1) lack of clarity on the identity of the critical counter-receptor responsible for T-cell suppression; 2) high clearance via target-mediated drug disposition (TMDD) by VISTA⁺ neutrophils and monocytes at physiologic pH and; 3) cellular activation and cytokine release syndrome (CRS) at sub-therapeutic doses by engagement of VISTA in the blood.

Objective

• To prevent TMDD and mitigate potential CRS we developed SNS101, a human monoclonal IgG1 antibody specific for the protonated, active form of VISTA, and interrogated its inhibitory potential of VISTA interacting with proposed binding partners at low(6.0) and physiological pH (7.4)
• Potential for CRS was tested in vitro as well as in vivo in a humanized mouse model
• Pharmacokinetic (PK) profile and anti-tumor efficacy of SNS-101 in combination with anti-PD-1 was assessed in syngeneic tumor models utilizing target-expressing human VISTA knock-in (KI) mice