1060-High-Throughput Selection of Fast-Acting Protein Drugs

This research presents a novel high-throughput yeast display platform designed to engineer fast-acting covalent protein drugs that overcome the limitations of rapid systemic clearance. By integrating site-specific chemical crosslinkers with precise protein mutations, the authors successfully developed IB101, a potent PD-L1 antagonist, and IB201, a covalent IL-18 agonist. These engineered proteins achieve rapid target engagement and sustained receptor occupancy, leading to superior antitumor efficacy in vivo compared to traditional non-covalent antibodies. The study further demonstrates the platform's versatility by creating a fast-acting covalent variant of the SARS-CoV-2 RBD binder. Ultimately, this methodology establishes a general strategy for transforming various protein scaffolds into highly specific covalent therapeutics with enhanced pharmacodynamic properties.

References:

• Fan Q, Mei J, Li T, et al. A high-throughput selection system for fast-acting covalent protein drugs[J]. Science, 2026: eadv3081.