AET Poster: Balancing Innovation and Developability: A Dual Strategy for Delivering Clinical- Grade VHH Antibodies

Abstract

The discovery of therapeutic antibodies requires a careful balance between molecular innovation and downstream developability to ensure successful clinical translation. Single-domain antibodies (VHHs) offer unique advantages, including small size, high stability, and access to challenging epitopes, but their optimization must consider both functional performance and developability risks early in the pipeline. To address these challenges, integrated discovery strategies that combine rational engineering with immune derived diversity are increasingly valuable.

Engineering-based approaches enable precise control over sequence space and can support Freedom-to-Operate (FTO) objectives, while in vivo immunization campaigns leverage natural affinity maturation to generate high-quality binders with favourable biophysical properties. In this study, we implemented two complementary antibody discovery approaches targeting the same antigen: (i) an FTO-driven evolution of a parental VHH using targeted mutagenesis and display technologies, and (ii) a llama immunization campaign followed by library screening. By combining orthogonal strategies with early developability assessment, we aimed to maximize the likelihood of identifying robust, clinically relevant antibody candidates.