title: VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  HEK-TLR transfectants were used to compare the selectivity and potency of VTX-2337, imiquimod, CpG ODN2006, and CL075. 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 activate NK cell activity through direct and indirect mechanisms was also investigated. Finally, we tested the potential for VTX-2337 to augment antibody-dependent cell-mediated cytotoxicity (ADCC), especially in individuals with low-affinity FcγR3A single-nucleotide polymorphism (SNP).
  
  
  RESULTS
  VTX-2337 selectively activates TLR8 with an EC(50) of about 100 nmol/L and stimulates production of TNFα and interleukin (IL)-12 from monocytes and myeloid dendritic cells (mDC). VTX-2337 stimulates IFNγ production from NK cells and increases the cytotoxicity of NK cells against K562 and ADCC by rituximab and trastuzumab. Effects of VTX-2337 on NK cells were, in part, from direct activation as increased IFNγ production and cytotoxic activity were seen with purified NK cells. Finally, VTX-2337 augments ADCC by rituximab in PBMCs with different FcγR3A genotypes (V/V, V/F, and F/F at position 158).
  
  
  CONCLUSIONS
  VTX-2337 is a novel small-molecule TLR8 agonist that activates monocytes, DCs, and NK cells. Through the activation of NK cells, it has the potential to augment the effectiveness of monoclonal antibody treatments where a polymorphism in FcγR3A limits clinical efficacy.
authors: Tumor Vaccine Group, Center for Translational Medicine in Women's Health, University of Washington, Seattle, Washington, USA.
authors: Hailing
authors: H
authors: Lu
authors: Gregory N
authors: GN
authors: Dietsch
authors: Maura-Ann H
authors: MA
authors: Matthews
authors: Yi
authors: Y
authors: Yang
authors: Smita
authors: S
authors: Ghanekar
authors: Margaret
authors: M
authors: Inokuma
authors: Maria
authors: M
authors: Suni
authors: Vernon C
authors: VC
authors: Maino
authors: Katherine E
authors: KE
authors: Henderson
authors: James Jeffry
authors: JJ
authors: Howbert
authors: Mary L
authors: ML
authors: Disis
authors: Robert M
authors: RM
authors: Hershberg
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D000077271:Imiquimod; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001552:Benzazepines; C513533:CpG ODN 2006; C496124:FCGR3A protein, human; D018836:Inflammation Mediators; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D017452:Receptors, IgG; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; C573973:VTX-2337; D018664:Interleukin-12; D000069283:Rituximab; D007371:Interferon-gamma; D000077271:Imiquimod