Description
Motolimod is an agonist of toll-like receptor 8 (TLR8). It increases the production of TNF-α and IL-12 in human peripheral blood mononuclear cells (PBMCs; EC
50s = 140 and 120 nM, respectively), monocytes, and myeloid dendritic cells. Motolimod also increases IFN-γ production in natural killer (NK) cells and increases cytolysis in K562 NK cell-sensitive leukemia cells when used at concentrations of 167 and 500 nM for 48 hours. It increases plasma levels of a group of human cytokines, including IL-6, IL-12p70, TNF-α, MCP-1, and MIP-1β, in NOD-
scid IL2rynull (NSG) mice reconstituted with human immune system (NSG-HIS) when administered at doses of 1.5 and 15 mg/m
2. Motolimod, when used in combination with pegylated liposomal doxorubicin (PLD), reduces tumor growth and increases tumor infiltration of monocytes and T cells in an ovarian cancer NSG-HIS mouse model.
in vivo
Monkeys receive a subcutaneous injection of Motolimod (1 or 10 mg/kg), and plasma is collected predose, 6, 12, 24, and 96 h post-injection. For the 10 mg/kg dose, mean plasma levels of IL-1β increase from baseline levels of 0.5 pg/mL, up to 9.12±2.7 ng/mL (p<0.05, t-test) at 6 h post-administration of Motolimod (10 mg/kg). Circulating levels of IL-18 also increase from a baseline of ~ 1 pg/mL to 68.7±4.4 pg/mL (p<0.05, t-test) at 6 h in response to the Motolimod (VTX-2337) treatment (10 mg/kg). Levels of IL-6 are monitored, as this mediator is induced in response to TLR8 activation, but the release is independent of NLRP3 inflammasome activation. In addition, plasma levels of IFNγ are assessed as a measure of NK cell activation in response to Motolimod treatment[2].
References
[1] HAILING LU. VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC.[J]. Clinical Cancer Research, 2012, 18 2: 499-509. DOI:
10.1158/1078-0432.ccr-11-1625[2] HAILING LU. TLR8 agonist VTX-2337 enhances NKG2D-mediated cytotoxicity of NK cells[J]. Journal for Immunotherapy of Cancer, 2013, 49 1: P44-P44. DOI:
10.1186/2051-1426-1-s1-p44[3] Z. J. RUTNAM. Motolimod, a selective TLR8 agonist induces apoptosis in monocytic myeloid-derived suppressor cells (M-MDSC)[J]. Journal for Immunotherapy of Cancer, 2015, 3 1: P296-P296. DOI:
10.1186/2051-1426-3-s2-p296[4] R. FERRIS. Active8: a randomized, double-blind, placebo-controlled study of chemotherapy plus cetuximab in combination with TLR8 agonist VTX-2337 in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN)[J]. Journal for Immunotherapy of Cancer, 2014, 2 1: P69-P69. DOI:
10.1186/2051-1426-2-s3-p69[5] B. MONK. Integrative Development of a TLR8 Agonist for Ovarian Cancer Chemoimmunotherapy[J]. Clinical Cancer Research, 2016, 23 1: 1955-1966. DOI:
10.1158/1078-0432.ccr-16-1453[6] G. DIETSCH. Coordinated Activation of Toll-Like Receptor8 (TLR8) and NLRP3 by the TLR8 Agonist, VTX-2337, Ignites Tumoricidal Natural Killer Cell Activity[J]. PLoS ONE, 2016, 11 1. DOI:
10.1371/journal.pone.0148764
