Fast and Accurate Antibody Sequence Design via Structure Retrieval

A BSTRACT Recent advancements in protein design have leveraged diffusion models to generate structural scaffolds, followed by a process known as protein inverse folding, which involves sequence inference on these scaffolds. However, these methodologies face significant challenges when applied to hyper-variable structures such as antibody Complementarity-Determining Regions (CDRs), where sequence inference frequently results in non-functional sequences due to hallucinations. Distinguished from prevailing protein inverse folding approaches, this paper introduces IgSeek, a novel structure-retrieval framework that infers CDR sequences by retrieving similar structures from a natural antibody database. Specifically, IgSeek employs a simple yet effective multi-channel equivariant graph neural network to generate high-quality geometric representations of CDR backbone structures. Subsequently, it aligns sequences of structurally similar CDRs and utilizes structurally conserved sequence motifs to enhance inference accuracy. Our experiments demonstrate that IgSeek not only proves to be highly efficient in structural retrieval but also outperforms state-of-the-art approaches in sequence recovery for both antibodies and T -Cell Receptors, offering a new retrieval-based perspective for therapeutic protein design. 1 M AIN Antibodies, known for their high specificity and affinity, have emerged as pivotal therapeutic agents in the treatment of complex diseases, including cancer Adams & Weiner (2005), autoimmune disorders Feldmann & Maini (2003), and infectious diseases Abraham (2020). In 2023, the global best-selling drug was Keytruda, a cancer treatment antibody, with sales reaching $25 billion, surpassing Humira, another antibody used for treating rheumatoid arthritis, which had dominated the market for the past decade (Dunleavy, 2024). Traditionally, the discovery of antibodies has predominantly relied on immunizing animals with antigens V an Wauwe et al. (1980) or employing various display techniques such as phage MacCallum et al. (1996) and yeast displays Chao et al. (2006). However, these approaches face significant challenges when dealing with structurally intricate proteins, which are difficult to express in a soluble and functional form. Additionally, even when numerous candidate antibodies are generated through these techniques, they may not necessarily bind to the desired domain or exhibit therapeutic efficacy.