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Diagnostic Technologies and Molecular and Cellular Profiling: Biomarker Assay Development, Validation, and Qualification

Talabostat augments IL-1ß and IL-1 production from peripheral blood monocytes isolated from healthy donors.

University of Colorado Health Sciences Center, Denver, CO and Point Therapeutics, Boston, MA

Abstract

A8

Talabostat (L-valine-L-boroproline), an orally active, potent inhibitor of dipeptidyl peptidases, is in clinical trials for treating non-small lung cancer, metastatic melanoma, chronic lymphocytic leukemia and pancreatic cancer. In a mouse model of melanoma using the B16-FO line, the anti-tumor effect of Talabostat is diminished in mice deficient for the type I IL-1 receptor. One mechanism for IL-1-dependent anti-tumor activity of Talabostat is to increase infiltrating inflammatory cells into the tumor. This mechanism also includes increased activity of immunological competent cells and the induction of anti-tumor immunity. In the present study, we hypothesized that macrophages and other IL-1-producing cells in the tumor are partially activated due to hypoxic changes or necrotic tissues. Furthermore, Talabostat would then augment the production and release of IL-1ß and IL-1ß would increase local IL-1 production. Local IL-1 production would also be primarily membrane IL-1, which in animal studies induces anti-tumor immunity. In order to mimic the partially activated macrophage in the tumor, we used peripheral blood mononuclear cells from healthy human subjects and stimulated these cells with very low concentrations of endotoxin (0.1 ng/mL) and measured the release of IL-1ß from the culture and the content of cell-associated IL-1. Using clinically relevant concentrations of Talabostat (1 M;M;) and 0.1 ng/mL of endotoxin, we observed a three-fold increase in IL-1ß release, and a two-fold increase in IL-1. A similar augmentation of IL-1ß was observed when peripheral blood mononuclear cells from healthy donors were stimulated with the Toll-like receptor agonist peptidoglycan isolated from Staphylococcus epidermidis. TNF production by LPS at 0.1 ng/mL was inhibited by 1 M;M Talabostat (85% reduction). In some donors, we observed that Talabostat (1 M;M;) increased IL-1ß production directly (without the presence of endotoxin) and attribute those who respond to Talabostat alone to have pre-activated monocytes.