By Mark McCoy
Biologics have had a leading role in recent ground-breaking advancements in the treatment of cancer, COVID19 , neurodegeneration and inflammatory disease. They are typically mAbs, directed at cell-surface or soluble ligands such as PD-1, SARS-COV-2 spike, Abeta protofibrils, IL23 and TNFa that block interactions, affect signaling, or target those proteins for degradation. New generations of biologics promise greater efficacy, less adverse effects and treatment of diseases with unmet need, attempting to improve outcomes using, for example, combinations of molecules, designing multifunctional proteins, chimeras and mutated/modified cytokines. These are complex molecules, each with unique challenges to discover and develop. The rapid progression of new modalities into development has expanded the need for more detailed understanding of therapeutic protein behavior and interactions, with high interest in methods, like NMR, that can be used under conditions relevant to formulation and process development.
We will show how data from multiple NMR experiments are used together to understand different aspects of protein behavior with a focus on new modality characterization, influencing projects at different discovery and development stages. Methods typically include diffusion filtered 1H, R1 and R2 measurements, protein DOSY and natural abundance 13C-edited sofast-HMQC. Areas where NMR data can affect decision-making include mechanism od action differentiation, developability assessments, co-formulation derisking, formulation optimization and DS/DP comparisons. In the spirit of practical applications, examples will be taken from our recent experience with Fc-fusions, bispecifics, multivalent VHHs, engineered cytokines and ADCs.