UBIQUIBODY PLATFORM FOR TARGETED DEGRADATION OF ONCOGENIC FUSION PROTEINS

UbiquiTx是一种新型mRNA治疗药物的先驱，它可以有效地、选择性地降解小分子降解剂无法靶向的靶标。泛素体（Ubiquibodies, uAbs）是一种蛋白质融合体，它可以结合到感兴趣的靶标上，并通过内源性泛素-蛋白酶体途径（UPP）对其进行靶向细胞内降解。这些新分子有望通过选择UPP来实现靶向蛋白质降解，从根本上改变药物发现和人类医学。UbiquiTx人工智能驱动的发现平台使数千种蛋白质靶点的芯片设计成为可能，加速了蛋白质降解剂在广泛临床适应症中的发展。在这个

UbiquiTx is pioneering a novel class of mRNA therapeutics that potently and selectively degrade targets not historically addressable by small-molecule degraders. Ubiquibodies (uAbs) are protein fusions that can bind to a target of interest and tag it for targeted intracellular degradation via the endogenous ubiquitin-proteasome pathway (UPP). These novel molecules promise to fundamentally transform drug discovery and human medicine by co-opting the UPP to achieve targeted protein degradation. UbiquiTx artificial intelligence-driven discovery platform enables in silico design of thousands of protein targets, accelerating the development of protein degraders across a broad range of clinical indications. In this project, UbiquiTx will design specific uAbs to selectively target and degrade FGFR2 fusions, a common genetic event in patients with intrahepatic cholangiocarcinoma (iCCA). Candidates will be encapsulated within LNP formulations to test delivery to iCCA cells and functional degradation capability. The feasibility of our approach is supported by our previous computation-mediated engineering of effective, peptide-based uAbs, as well as our recent work demonstrating the potential therapeutic benefit of FGFR2 degradation for the treatment of iCCA. Notably, the uAbs designed should be effective even in patients with acquired resistance to small molecule FGFR inhibitors because of secondary mutations in the FGFR tyrosine kinase domain.