VTX-2337 Is a Novel TLR8 Agonist That Activates NK Cells and Augments ADCC

• Published in: Clinical cancer research 2012-01, Vol.18 (2), p.499-509
• Main Authors: HAILING LU, DIETSCH, Gregory N, DISIS, Mary L, HERSHBERG, Robert M, MATTHEWS, Maura-Ann H, YI YANG, GHANEKAR, Smita, INOKUMA, Margaret, SUNI, Maria, MAINO, Vernon C, HENDERSON, Katherine E, HOWBERT, James Jeffry
• Format: Article
• Language: English
• Subjects: Aminoquinolines - pharmacology; Antibodies, Monoclonal, Murine-Derived - pharmacology; Antibody-Dependent Cell Cytotoxicity - drug effects; Antineoplastic agents; Antineoplastic Agents - pharmacology; Benzazepines - pharmacology; Biological and medical sciences; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Drug Synergism; HEK293 Cells; Humans; Inflammation Mediators - metabolism; Interferon-gamma - biosynthesis; Interleukin-12 - biosynthesis; Interleukin-12 - secretion; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - secretion; Medical sciences; NF-kappa B - metabolism; Oligodeoxyribonucleotides - pharmacology; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Receptors, IgG - genetics; Receptors, IgG - metabolism; Rituximab; Toll-Like Receptor 8 - agonists; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - secretion
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-1625

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. 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). 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). 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.