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An immunotherapeutic composed of a monoclonal antibody directed against the tumor-associated antigen (TAA) human epidermal growth factor receptor 2 (EGFR2; HER2; ErbB2) conjugated to a Toll-like receptor 8 (TLR8; CD288) agonist, with potential immunostimulating and antineoplastic activities. Upon intravenous administration of the HER2-directed TLR8 agonist SBT6050, the anti-HER2 monoclonal antibody targets and binds to HER2 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). This 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, activation of cytolytic natural killer (NK) cells and neutrophils, and the induction of a 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. HER2, a tyrosine kinase receptor, is overexpressed by many cancer cell types.
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