Abstract 4233: Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity

Abstract

Abstract The tumor specific activation of natural killer (NK) cells is an area of active investigation in immune oncology, but to date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies). NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles® are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to identify Bicycles® that bind specifically to the key activating receptor, NKp46. When chemically coupled to tumor antigen binding Bicycles, this results in highly potent, antigen-dependent receptor activation and NK cell activation. We term this new class of fully synthetic molecules NK-TICAs and we will describe herein their discovery and evaluation.We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA™ compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner.In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA™ as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors. The data presented here provide initial proof of concept for the application of our Bicycle technology to drive NK cell-mediated tumor immunity. Citation Format: Fay J. Dufort, Christopher J. Leitheiser, Gemma Mudd, Julia Kristensson, Alexandra Rezvaya, Katie Gaynor, Sandra Uhlenbroich, Liudvikas Urbonas, Heather Scott, Liuhong Chen, Helen Harrison, Michael Skynner, Kevin McDonnell, Philip E. Brandish, Nicholas Keen. Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule designed to induce targeted tumor cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4233.