Harnessing Synthetic Peptides for CD137 Activation: A New Approach to Cancer Immunotherapy

CD137 is a member of the TNF receptor family that supports T and NK cell signaling. Anti-CD137 antibodies have demonstrated significant anti-tumor effects in preclinical studies, primarily through cytotoxic T cells and memory response induction. Clinical trials are underway for two antibodies, urelumab and utomilumab; urelumab has shown partial responses but has been limited by liver toxicity, while utomilumab has not shown significant single-agent activity.

A novel drug class, Bicycles, are fully synthetic, constrained peptides with high affinity and specificity that are not achievable with traditional small molecules. This platform leverages phage display and chemical optimization to rapidly develop binders with desirable properties. The small size of Bicycles facilitates better tumor penetration and rapid renal clearance, potentially avoiding liver and gastrointestinal toxicity associated with other drugs.

We explored a synthetic Bicycle CD137 agonist that could potentially activate anti-tumor responses without causing liver toxicity. A high affinity lead compound, BCY3814, was identified after screening and optimization. It competes with the CD137 ligand and utomilumab for binding but not with urelumab, which binds a different site. Given that CD137 activation requires receptor crosslinking, we developed multiple valent variants of BCY3814 using chemical linkers and hinges, resulting in a range of potent and efficacious molecules in cell-based assays. Some of these Bicycles were more potent than clinical antibodies or the natural ligand and are being tested in a humanized mouse model for anti-tumor activity and reduced liver toxicity.

The study suggests that these synthetic agonists could be promising candidates for cancer immunotherapy and may lead to the development of synthetic agonists for other TNF receptors. The research was presented at the American Association for Cancer Research Annual Meeting in 2018.