De novo design of hundreds of functional GPCR-targeting antibodies enabled by scaling test-time compute

Abstract We present significant advances in de novo antibody design against G protein-coupled receptors (GPCRs) enabled by scaling the test-time compute used by our generative protein design system, JAM. We de novo design hundreds of VHH (single domain) antibodies against CXCR4 and CXCR7, with top designs showing picomolar to low-nanomolar affinities, high selectivity, and favorable early-stage developability profiles, matching or outperforming clinical-stage molecules in these dimensions. Further, high affinity designs potently modulate receptor function, with most acting as antagonists (inhibitors) and, strikingly, a subset functioning as agonists (activators) of CXCR7 — the first antibody agonists reported for this receptor, and the first computationally designed antibody GPCR agonists of any kind. Using a single experimentally validated agonist to further prompt JAM, we generate over 300 additional diverse agonists with superior properties, including a design with agonism EC50 rivaling that of CXCR7’s natural ligand, SDF1α. These results show that increasing the “reasoning” capacity of biomolecular generative models by scaling test-time computation will enable them to solve increasingly difficult problems in drug design.