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Augments ADCC VTX-2337 Is a Novel TLR 8 Agonist That Activates NK Cells and Updated

Purpose: We aim to characterize VTX-2337, a novel Toll-like receptor (TLR) 8 agonist in clinical development, and investigate its potential to improve monoclonal antibody–based immunotherapy that includes the activation of natural killer (NK) cells. Experimental Design:HEK-TLR transfectants were used to compare the selectivity and potency of VTX2337, imiquimod, CpGODN2006, andCL075. The ability of VTX-2337 to induce cytokine and chemokine production from human peripheral blood mononuclear cells (PBMC) and activation of specific immune cell subsets was examined. The potential for VTX-2337 to activateNK cell activity through direct and indirect mechanisms was also investigated. Finally, we tested the potential for VTX-2337 to augment antibodydependent cell-mediated cytotoxicity (ADCC), especially in individuals with low-affinity FcgR3A singlenucleotide polymorphism (SNP). Results: VTX-2337 selectively activates TLR8 with an EC50 of about 100 nmol/L and stimulates production of TNFa and interleukin (IL)-12 from monocytes and myeloid dendritic cells (mDC). VTX2337 stimulates IFNg production from NK cells and increases the cytotoxicity of NK cells against K562 and ADCCby rituximab and trastuzumab. Effects of VTX-2337onNK cellswere, in part, fromdirect activation as increased IFNg production and cytotoxic activity were seen with purified NK cells. Finally, VTX-2337 augments ADCC by rituximab in PBMCs with different FcgR3A genotypes (V/V, V/F, and F/F at position