789 Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule to enhance targeted tumor cytotoxicity

Background Natural killer (NK) cells are immune that can detect and eliminate tumor bridge innate to adaptive responses. Tumor specific activation of NK is thus an area active investigation in oncology, but date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies), each which inherent disadvantages this application. Thus, alternative approaches warranted. Bicycle® small (ca. 1.5 kDa), chemically synthetic, structurally constrained peptides discovered via phage display optimized using structure-driven design medicinal chemistry approaches. We have now applied technology identify Bicycles bind specifically the key activating receptors, NKp46 CD16a. When coupled antigen binding results highly potent, antigen-dependent receptor activation. term new class fully synthetic molecules natural killer- tumor-targeted agonists (NK-TICAs™) we will describe their discovery evaluation presentation. Methods Using our unique screening platform, identified high affinity, selective binders By conjugating cell-engaging a model EphA2-binding Bicycle®, developed bifunctional Bicycle NK-TICA™ molecule. In vitro functional assays, evaluated ability NK-TICAs™ induce as well cell-mediated cytotoxicity cytokine production NK-tumor co-culture assays. Results novel modular compound with affinity selectivity receptors targeting capability. demonstrate receptor-expressing capability molecule function. With Bicycle's compound, engagement cells, function enhanced EphA2-expressing cytotoxicity, dose dependent manner. Conclusions therapeutic agents capable enhancing landscape oncology. hypothesize utilization multifunctional engager promote modulation infiltration anti-tumor activity solid tumors. The data presented here provide initial proof concept for application drive immunity.