SORS/WomenInBSC: epitope engineering and natural variation in antibody-antigen recognition

Abstract

Antibody–antigen interactions are central to modern immunotherapies. While efforts have focused on enhancing antibody binding to improve targeting, an emerging strategy involves engineering cell surface antigens to evade recognition. This 'cell shielding' approach enables selective targeting by protecting healthy cells from therapeutic antibodies, opening new possibilities for immune engineering and disease treatement. In this talk, I will present an application of epitope engineering in acute myeloid leukemia. Our work demonstrates that engineering a CD45 epitope enables transplanted hematopoietic stem cells to resist the effects of a potent antibody–drug conjugate (ADC), allowing for the targeted elimination of malignant cells while preserving normal hematopoiesis. This work prompts a broader question: how resilient are antibody therapies to natural variation in their target epitopes? To address this, we conducted a systematic analysis of natural single nucleotide variants (SNV) and their impact on antigen recognition across a broad panel of therapeutic antibodies, both approved and in clinical development. For every antibody analysed, we identified multiple missense SNVs within or near the antibody-antigen interface, a subset of which were predicted and experimentally confirmed to abolish antibody binding entirely. Although many of these variants are globally rare, some are enriched in specific populations, with important implications for patient stratification, therapy design and clinical decision-making.