Accelerating discovery and rational engineering of antibody modalities using Cryo- EM

TL;DR

Cryo-EM is transforming antibody drug discovery by enabling detailed structural insights and accelerating the design of next-generation therapeutics.

Contribution

The paper introduces Cryo-EM Polyclonal Epitope Mapping (Cryo-EMPEM) as a novel workflow for characterizing immunogenicity of antibody therapeutics and vaccines.

Findings

Cryo-EM provides accurate epitope mapping at the single amino acid level.

Cryo-EM complements AI/ML tools in the design of next-generation antibody therapeutics.

Cryo-EM is broadly applicable to monoclonal, bi-specific, and CAR binder antibody formats.

Abstract

As the need for novel therapeutic modalities is growing, researchers require innovative strategies and transformative technologies to overcome the limitations of traditional antibody discovery methodologies. Cryo-electron microscopy (Cryo-EM) has been successfully established as a powerful technique to accelerate antibody drug discovery processes. Despite the recent adoption of cryo-EM in drug discovery efforts, multiple cryo-EM supported therapies have already entered the clinics. The broad applicability of single particle imaging underpins the rapidly increasing implementation of cryo-EM in antibody drug discovery pipelines including monoclonal antibodies, design of bi- and multi-specific formats, and design of CAR binders for CAR-T cell therapy. Here, we will provide specific and diversified applications of cryo-EM that will contribute to reshape the future of antibody research. We will share how cryo-EM based epitope mapping provide accurate information at the single amino acids. We will explain ways one can leverage cryo-EM structures to design of next-generation antibody therapeutics. We will discuss our view on how cryo- EM can provide experimental complementation to Artificial Intelligence/Machine Learning (AI/ML) tools. Finally, we will touch base to cryo-EM Polyclonal Epitope Mapping (Cryo-EMPEM), a workflow that allowed to structurally characterize immunogenicity of antibody therapeutics and vaccines.