Nectin-4-directed TLR8 agonist SBT6290

An immunotherapeutic composed of a monoclonal antibody directed against the cell surface adhesion molecule and tumor-associated antigen (TAA) nectin-4 (PVRL4) conjugated to a Toll-like receptor 8 (TLR8; CD288) agonist, with potential immunostimulating and antineoplastic activities. Upon administration of the nectin-4-directed TLR8 agonist SBT6290, the anti-nectin-4 monoclonal antibody targets and binds to nectin-4 expressed on tumor cells, thereby localizing the TLR8 agonist directly to the tumor site. In turn, the TLR8 agonist moiety binds to TLR8 expressed on myeloid cells within the tumor microenvironment (TME). This activates myeloid cells, including tumor-associated macrophages (TAMs), myeloid cell-derived suppressive cells (MDSCs), and conventional dendritic cells (cDCs), and may lead to the activation of nuclear factor NF-kappa-B, the production of pro-inflammatory cytokines and chemokines, macrophage-induced tumor cell killing, inflammasome activation, the activation of cytolytic natural killer (NK) cells and neutrophils, and the induction of a T-helper cell type 1 (Th1)-weighted anti-tumor immune response. It also reverses the suppression of senescent naive and tumor-specific T-cells, and enhances the anti-tumor cytotoxic T-lymphocyte (CTL) immune response. TLR8, like other TLRs, recognizes pathogen-associated molecular patterns (PAMPs) and plays a key role in innate and adaptive immunity. Nectin-4, a TAA belonging to the nectin family, is overexpressed in a variety of cancers, but has a restricted distribution in normal tissue.