Distinguished Medical Engineering Seminar
Protein aggregates and potential immunogenicity in biotherapeutics
The goal of protein therapeutic development is the production of a drug that is safe and efficacious. This means understanding what the critical quality attributes (CQA) are; what modifications and degradants need to be controlled and which have no effect on safety or efficacy of the protein. Protein aggregates have the potential to be a CQA, as they could be immunogenic or differ in potency relative to the monomer. In this talk I'll describe studies we've done at Amgen to determine the relative risk of immunogenicity of different types of protein aggregates in the 50 nm to 10 micrometer size range. This included using different types of stress to generate protein aggregates, characterizing the aggregates, and testing them in in vitro and in vivo model systems. The results of these studies suggest that the size, amount of chemical modification, conformation, and dosage all play a role in the relative immunogenicity of protein aggregate, and that in vivo the immune response is weak and transient. This approach can be used to test other product quality attributes, types of particles, etc. as well.
Linda received her BS Chemistry from the Univ. of Michigan, and her PhD in Biological Chemistry from UCLA, specializing in protein structure function studies, purification and characterization (especially biophysical characterization). She joined Amgen over 30 years ago, and has been involved in the characterization of protein therapeutics throughout her career. This has included leading the biophysics and forensics (identification and root cause analysis for particle nonconformance) group which provided higher order structure analyses for all phases of protein development for over a decade, developed the early candidate selection strategy, and engineering universal scaffoldings. She is currently a Scientific Executive Director in the Attribute Science group in Process Development, where her primary responsibility is in the technology development efforts of this organization, especially cross functional and external collaborations, and educational outreach. Her primary areas of research/interest include protein structure/function relationships, development and implementation of predictive assays for protein stability to process, storage, and delivery conditions, and of assays to assess biological consequences of product quality attributes, especially protein aggregates. Linda is the chair of the AAPS focus group on Protein Aggregation and Biological Consequences, is a member of the USP expert committee on subvisible particle analysis for Biologics, is an adjunct professor at UCSB, and is on the editorial boards for J. Biological Chemistry and J. Pharm. Sci. She has published more than 130 articles in peer reviewed journals, authored many book chapters, and edited 2 books, on the subjects of protein folding, stability, and aggregation, potential immunogenicity of protein aggregates, and biotherapeutic development.