Background:

Target: TLR8

IC50: 100 nM (EC50)

Motolimod (VTX-2337) is a small molecule, selective Toll-like receptor (TLR) 8 agonist with EC50 value of 100 nM [1]. VTX-2337 is currently in clinical development as an immunotherapy for multiple oncology indications, including ovarian cancer and squamous cell carcinoma of the head and neck [2]. TLR8 is located in the endosome where it functions in the recognition of foreign nucleic acids from intracellular pathogens. TLR8 has emerged as a potential target for anticancer immunotherapies [1].

In vitro: VTX-2337 (800 nmol/L) activated NK cells, leading to increased TNFα and IL-12, IFNγ production and VTX-2337 (167 or 500 nmol/L) augmented rituximab- and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) [1]. Moreover, VTX-2337 (3 or 10 μM) induced mature IL-1β and IL-18 production through NLRP3 inflammasome activation in THP-1 cells [2].

In vivo: VTX-2337 (1 or 10 mg/kg, subcutaneous injection) induced IL-1β and IL-18 production in male cynomolgus monkeys [2].

Clinical trial: In a phase I dose-finding study, VTX-2337 (0.1–3.9 mg/m2, subcutaneous administration) was well tolerated and active with a predictable pharmacologic profile in adult subjects with advanced solid tumors or lymphoma [3].

参考文献:
1.  Lu H, Dietsch GN, Matthews MA, Yang Y, Ghanekar S, Inokuma M, et al. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin Cancer Res. 2012;18(2):499-509.
2.  Dietsch GN, Lu H, Yang Y, Morishima C, Chow LQ, Disis ML, et al. Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity. PLoS One. 2016;11(2):e0148764.
3.  Northfelt DW, Ramanathan RK, Cohen PA, Von Hoff DD, Weiss GJ, Dietsch GN, et al. A phase I dose-finding study of the novel Toll-like receptor 8 agonist VTX-2337 in adult subjects with advanced solid tumors or lymphoma. Clin Cancer Res. 2014;20(14):3683-91.