Bennett, N. R.; Watson, J. L.; Ragotte, R. J.; Borst, A. J.; See, D. L.; Weidle, C.; Biswas, R.; Shrock, E. L.; Leung, P. J. Y.; Huang, B.; Goreshnik, I.; Ault, R.; Carr, K. D.; Singer, B.; Criswell, C.; Vafeados, D.; Garcia Sanchez, M.; Kim, H. M.; Vazquez Torres, S.; Chan, S.; Baker, D.

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 (VHH\'s) that bind user-specified epitopes. We experimentally confirm binders to four 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.