NanoDesigner: Resolving the complex-CDR interdependency with iterative refinement

Camelid heavy-chain only antibodies consist of two heavy chains and single variable domains (VHHs), which retain antigen-binding functionality even when isolated. The term "nanobody" is now more generally used for describing small, single-domain antibodies. Several antibody generative models have been developed for the sequence and structure co-design of the complementary-determining regions (CDRs) based on the binding interface with a target antigen. However, these models are not tailored for nanobodies and are often constrained by their reliance on experimentally determined antigen-antibody structures, which are labor-intensive to obtain. Here, we introduce NanoDesigner, a tool for nanobody design and optimization based on generative AI methods. NanoDesigner integrates key stages -- structure prediction, docking, CDR generation, and side-chain packing -- into an iterative framework based on an expectation maximization (EM) algorithm. The algorithm effectively tackles an interdependency challenge where accurate docking presupposes a priori knowledge of the CDR conformation, while effective CDR generation relies on accurate docking outputs to guide its design. NanoDesigner approximately doubles the success rate of de novo nanobody designs through continuous refinement of docking and CDR generation.