Enhanced TRAIL Receptor Agonist APG350: Dimerization for Tumor Therapy Advancement

TRAIL, a member of the Tumor Necrosis Factor Superfamily, is a promising molecule for cancer therapy due to its selective induction of apoptosis in tumor cells. APG350, a novel TRAIL-receptor agonist, is composed of two single-chain binding domains, each with three TRAIL protomers linked together, and is dimerized through the Fc portion of human IgG1. This design results in six receptor binding sites, enhancing its binding to TRAIL receptors and its capacity for apoptosis induction in a variety of human cancer cells, including stem cells and primary tumors. In comparison to other clinical candidates, APG350's unique clustering ability on target cells sets it apart.

In vitro studies have demonstrated APG350's superior apoptotic induction compared to recombinant TRAIL and TRAIL-R2 specific antibodies. Pharmacokinetic analysis in mice and monkeys revealed a significantly longer half-life for APG350, indicating improved pharmacokinetics. In vivo studies in mice with Colo205 xenograft tumors showed that APG350 was more effective in reducing tumor volume and increasing the number of tumor-free animals, even in cases with large initial tumor sizes. Notably, APG350 also displayed potent anti-tumor efficacy against colon cancer stem cell-derived tumors and was well-tolerated in both mice and monkeys.

Additionally, APG350 has shown effectiveness in treating slowly growing primary rectum tumor xenografts, with significant tumor volume reduction observed. The general tolerability and potential liver toxicity of APG350 were assessed through co-application with a crosslinking antibody, resulting in only minor clinical signs at high doses without a significant increase in liver enzymes. Ongoing non-GLP toxicology studies are aimed at further confirming APG350's tolerability.

The study was presented at the 102nd Annual Meeting of the American Association for Cancer Research and published in the Cancer Research journal.