The paper describes Sensei Biotherapeutics’ approach to the discovery and development of SNS-101, which was designed to potently and selectively target the active protonated form of VISTA, a protein that plays a significant role in suppressing T-cell activation. VISTA was previously considered undruggable due to its extensive expression on myeloid cells, leading to safety issues such as cytokine release syndrome (CRS), in addition to a pharmacokinetic sink, which poses a significant challenge in reaching therapeutically relevant concentrations. The paper details the mechanism and characteristics of SNS-101, a novel pH-sensitive monoclonal antibody. SNS-101 was shown to bind to a novel epitope of VISTA that is remodeled under low pH conditions, switching VISTA into an active state that engenders extensive T-cell suppression. SNS-101 is designed to block VISTA by inhibiting its interaction with PSGL-1 on T-cells resulting in T-cell activation. Subsequently, in various preclinical models, SNS-101 was shown to mitigate CRS risk and maintain a favorable pharmacokinetic and safety profile, all of which had thwarted the clinical development of first generation, non-pH sensitive anti-VISTA antibodies.
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