“The data published in JITC describe the application of Bicycle’s unique technology to produce a new class of potential immuno-oncology therapies: tumor-targeted immune cell agonists, or TICAs,” said
The article outlines the work Bicycle is undertaking to unlock a new method of cancer immunotherapy via small molecule agonism of TNF superfamily receptors. In the studies, TICAs were evaluated in a suite of in vitro and in vivo assays to characterize the pharmacology and mechanism of action. Results showed that by linking a costimulatory receptor (e.g., CD137) targeting Bicycle to a tumor antigen (e.g., EphA2), targeting Bicycle potent agonists were created, which activated the costimulatory receptor selectively in the presence of tumor cells expressing that antigen. An EphA2/CD137 TICA efficiently co-stimulated human peripheral blood mononuclear cells in vitro in the presence of EphA2-expressing tumor cell lines, as measured by an increased secretion of interferon γ and interleukin-2. Treatment of C57/Bl6 mice (transgenic for the human CD137 extracellular domain, huCD137) bearing EphA2-expressing MC38 tumors resulted in increased infiltration of CD8+ T cells, the elimination of tumors, and generation of immunological memory. Tumor target-dependent CD137 agonism using TICAs afforded elimination of tumors in preclinical models using only intermittent dosing, suggesting the potential for a wide therapeutic index in humans.
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