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Developing therapeutic antibodies is a challenging endeavor, often requiring large-scale screening to produce initial binders, that still often require optimization for developability. We present a computational pipeline for the discovery and design of therapeutic antibody candidates, which incorporates physics- and AI-based methods for the generation, assessment, and validation of candidate antibodies with improved developability against diverse epitopes, via efficient few-shot experimental screens. We demonstrate that these orthogonal methods can lead to promising designs. We evaluated our approach by experimentally testing a small number of candidates against multiple SARS-CoV-2 variants in three different tasks: (i) traversing sequence landscapes of binders, we identify highly sequence dissimilar antibodies that retain binding to the Wuhan strain, (ii) rescuing binding from escape mutations, we show up to 54% of designs gain binding affinity to a new subvariant and (iii) improving developability characteristics of antibodies while retaining binding properties. These results together demonstrate an end-to-end antibody design pipeline with applicability across a wide range of antibody design tasks. We experimentally characterized binding against different antigen targets, developability profiles, and cryo-EM structures of designed antibodies. Our work demonstrates how combined AI and physics computational methods improve productivity and viability of antibody designs.

Original publication

DOI

10.1080/19420862.2025.2511220

Type

Journal article

Journal

MAbs

Publication Date

12/2025

Volume

17

Keywords

Antibody design, artificial intelligence, immunology, mab, structural biology, SARS-CoV-2, Humans, COVID-19, Spike Glycoprotein, Coronavirus, Mutation, Antibodies, Viral, Antibodies, Monoclonal, Epitopes, Antibodies, Neutralizing, Drug Design, COVID-19 Drug Treatment