IgCraft: A versatile sequence generation framework for antibody discovery and engineering

Designing antibody sequences to better resemble those observed in natural human repertoires is a key challenge in biologics development. We introduce IgCraft: a multi-purpose model for paired human antibody sequence generation, built on Bayesian Flow Networks. IgCraft presents one of the first unified generative modeling frameworks capable of addressing multiple antibody sequence design tasks with a single model, including unconditional sampling, sequence inpainting, inverse folding, and CDR motif scaffolding. Our approach achieves competitive results across the full spectrum of these tasks while constraining generation to the space of human antibody sequences, exhibiting particular strengths in CDR motif scaffolding (grafting) where we achieve state-of-the-art performance in terms of humanness and preservation of structural properties. By integrating previously separate tasks into a single scalable generative model, IgCraft provides a versatile platform for sampling human antibody sequences under a variety of contexts relevant to antibody discovery and engineering. Monoclonal antibodies are an important class of therapies that comprise an increasingly large share of the global pharmaceutical market (Ecker et al., 2015). Key to the success of these molecules as therapeutics lies not only in their ability to selectively bind their target with high affinity, but also in their favorable developability, a property that broadly describes the suitability of a functional compound to become a viable drug, often a function of immunogenicity, solubility, and a number of other factors. Conventional antibody discovery typically relies on either animal immunization (Lee et al., 2014) or high-throughput screening of large sequence libraries (Bradbury et al., 2011) to isolate potential candidates. While in vitro screening methods are faster, cheaper, and have ethical advantages compared to immunization, naturally-derived antibodies tend to exhibit better developa-bility properties, including favorable pharmacokinetics, high specificity, and low immunogenicity (Jain et al., 2017).