“Atomically Accurate de Novo Design of Single-Domain Antibodies”, Nathaniel R. Bennett, Joseph L. Watson, Robert J. Ragotte, Andrew J. Borst, Déjenaé L. See, Connor Weidle, Riti Biswas, Ellen L. Shrock, Philip J. Y. Leung, Buwei Huang, Inna Goreshnik, Russell Ault, Kenneth D. Carr, Benedikt Singer, Cameron Criswell, Dionne Vafeados, Mariana Garcia Sanchez, Ho Min Kim, Susana Vázquez Torres, Sidney Chan, David Baker2024-03-18 (diffusion model, AlphaFold)⁠:

Despite the central role that antibodies play in modern medicine, there is currently no way to rationally design novel antibodies to bind a specific epitope on a target. Instead, antibody discovery currently involves time-consuming immunization of an animal or library screening approaches.

Here we demonstrate that a fine-tuned RFdiffusion network is capable of designing de novo antibody variable heavy chains (VHHs) that bind user-specified epitopes.

We experimentally confirm binders to 4 disease-relevant epitopes, and the cryo-EM structure of a designed VHH bound to influenza hemagglutinin is nearly identical to the design model both in the configuration of the CDR loops and the overall binding pose.