Abstract ND02: BT7480: A completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137

BT7480, a completely novel fully tumor antigen (Nectin-4) dependent agonist of the immune cell costimulatory receptor CD137. It is also the first example (to our knowledge) of a fully synthetic, low MW (~7.5kDa, less than 1/20th of an IgG), peptide-based approach to targeting either Nectin-4 or CD137. The costimulatory immune receptor CD137 has been recognized for its potential as a drug target in cancer alongside checkpoint inhibitors, but this promise has not been realized for patients due to toxicity (principally hepatic toxicity) and limited efficacy of current biologic based therapies. Thus, alternative approaches to this important target are warranted. Bicycles® are small, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied this disruptive technology to the problem, identifying CD137 binding Bicycles and chemically linking these to specific tumor antigen binding Bicycles to generate multifunctional “bi-specific” like molecules that induce tumor antigen dependent, tumor localized agonism of CD137. We termed these Tumor-targeted Immune Cell Agonists (TICAs™). BT7480 is a TICA that was designed to deliver highly potent CD137 agonism to Nectin-4 overexpressing tumor tissue. Nectin-4 is expressed at high levels in bladder, breast and lung tumors and at low levels in normal tissue and thus is an attractive target for localized immunotherapy. BT7480 binds potently to Nectin-4 expressing cells and engages CD137 expressed on immune cells in trans, leading to potent Nectin-4-dependent CD137 agonism in primary human PBMC/tumor cell co-culture assays. Treatment of Nectin-4 expressing tumors in immunocompetent mice with BT7480 induces complete tumor regressions and subsequent resistance to tumor re-challenge. Time-course examination of the treated tumors revealed a unique mechanism of action - rapid activation of myeloid cells (