Strategies that activate cytotoxic T-cells dramatically improve outcomes in cancer. However, prolonged immunomodulation can be severely toxic and lead to T-cell exhaustion, which is a problem amplified by the long half-life of antibodies. This issue is compounded in combination therapy using multiple biological therapeutics. Bicycles can either disrupt or promote the protein-protein interactions inherent in T-cell modulation while avoiding many of the liabilities associated with antibodies. They can rapidly penetrate tumours, are easy to manufacture, avoid liver metabolism and Fc-mediated interactions, and have tuneable exposure to optimise combination therapy and sequencing.
We have identified potent Bicycle activators of CD137, a TNF receptor family member that acts to activate (“co-stimulate”) T-cells. Bicycle agonists represent a unique approach in this space that should circumvent the limitations (hepatotoxicity and limited efficacy) of antibodies and better enable combination therapy. We are exploring additional co-stimulatory and checkpoint inhibitor approaches.