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.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
