Zero-shot antibody design in a 24-well plate

Despite breakthroughs in protein design enabled by artificial intelligence, reliably designing functional antibodies from scratch has remained an elusive challenge. Recent works show promise but still require large-scale experimental screening of thousands to millions of designs to reliably identify hits. In this work, we introduce Chai-2, a multimodal generative model that achieves a 16% hit rate in fully de novo antibody design, representing an over 100-fold improvement compared to previous computational methods. We prompt Chai-2 to design[≤] 20 antibodies or nanobodies to 52 diverse targets, completing the workflow from AI design to wet-lab validation in under two weeks. Crucially, none of these targets have a preexisting antibody or nanobody binder in the Protein Data Bank. Remarkably, in just a single round of experimental testing, we find at least one successful hit for 50% of targets, often with strong affinities and favorable drug-like profiles. Beyond antibody design, Chai-2 achieves a 68% wet-lab success rate in miniprotein design - routinely yielding picomolar binders. The high success rate of Chai-2 enables rapid experimental validation and characterization of novel antibodies in under two weeks, paving the way toward a new era of rapid and precise atomic-level molecular engineering. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=56 SRC="FIGDIR/small/663018v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@69655borg.highwire.dtl.DTLVardef@17d44dborg.highwire.dtl.DTLVardef@133b7ddorg.highwire.dtl.DTLVardef@6c4319_HPS_FORMAT_FIGEXP M_FIG 52 antigens targeted by Chai-2. Blue boxes indicate targets with at least one successful binder out of [≤]20 assayed designs, representing 50% of the tested targets. Date: June 30, 2025 C_FIG