Approach

VISTA, a B7 family ligand, has been recognized for years as an important immune checkpoint that is primarily expressed on myeloid cells, which are a hub of immunosuppressive activity in cold, T cell-excluded tumors. VISTA has been difficult to drug selectively because it is abundantly displayed on noncancerous myeloid cells throughout the body, such as neutrophils, monocytes, and macrophages. Indiscriminately blocking VISTA renders these cells a pharmacokinetic sink, depleting drug levels in the bloodstream before they are able to reach the tumor, and can also trigger cytokine release syndrome as these immune cells react to on-target/off-tumor inactivation of the checkpoint

SNS-101 is designed to bind only within the low pH of the tumor microenvironment. It operates through two mechanisms:

• The Fab domain prevents checkpoint suppression of T cells by blocking the binding of VISTA to the T cell protein PSGL-1.
• The Fc domain binds to Fc gamma receptors on myeloid cells, increasing their anti-tumor activity through the release of pro-inflammatory cytokines.