Nabla Bio, | bioRxiv Science

bioRxiv2025

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

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 CXCR7s natural ligand, SDF1. 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.

synthetic biology↗

bioRxiv2025

De novo design of epitope-specific antibodies against soluble and multipass membrane proteins with high specificity, developability, and function

We present JAM, a generative protein design system that enables fully computational design of antibodies with therapeutic-grade properties for the first time. JAM generates antibodies de novo in both single-domain (VHH) and paired (scFv/mAb) antibody formats that achieve double-digit nanomolar affinities, strong early-stage developability profiles, and precise epitope targeting without experimental optimization. We demonstrate JAMs capabilities across multiple therapeutic contexts, including the first fully computationally designed antibodies to multipass membrane proteins - Claudin-4 and CXCR7. Against SARS-CoV-2, JAM-designed antibodies achieved sub-nanomolar pseudovirus neutralization potency, with early stage developability metrics achieving established clinical benchmarks. We show that increasing test-time computation by allowing JAM to iteratively introspect on its outputs substantially improves both binding success rates and affinities, representing the first evidence that test-time compute scaling may extend to physical protein design systems. The entire process from design to recombinant characterization requires <6 weeks, and multiple targets can be pursued in parallel with minimal additional experimental overhead. These results establish de novo antibody design as a practical approach for therapeutic discovery, offering paths to both improved efficiency in standard workflows and new opportunities for previously intractable targets. Disclaimer: While we provide detailed descriptions of experimental methods and success metrics, we choose not disclose methodological details of JAM for commercial reasons.

bioengineering↗