Biophysical Characterization and Immunogenic Risk of Therapeutic Protein Aggregates

Nicole Jarvi

I am pictured presenting my undergraduate research project mentored by Dr. Balu-Iyer at the UB Celebration of Student Excellence in 2018. This project sparked my interest in scientific research and motivated me to pursue a career as a research scientist in the biopharmaceutical industry.

I am pictured presenting my undergraduate research project mentored by Dr. Balu-Iyer at the UB Celebration of Student Excellence in 2018. This project sparked my interest in scientific research and motivated me to pursue a career as a research scientist in the biopharmaceutical industry.

Graduate Student Project

Introduction

Biologics, including monoclonal antibodies and recombinant proteins, top the global drug market and gross billions of dollars every year. However, the remarkable treatment success seen for these drugs is limited in certain patient populations due to development of an anti-drug antibody response.

My name is Nicole Jarvi. I'm a first-year PhD student at UB in the Department of Pharmaceutical Sciences. I joined Dr. Balu-Iyer's laboratory in my undergrad and I graduated from the MS program in the department in 2019 under his mentorship. Dr. Balu-Iyer's lab investigates the risk factors and mechanisms of unwanted immune response towards therapeutic proteins (also known as immunogenicity), and we develop strategies to induce immune tolerance towards those proteins.

Safety risks and loss of clinical response make anti-drug antibodies a serious issue. The presence of protein aggregates or particulates within biologic products has gained considerable interest by the FDA as a risk factor. With the goal of prevention or mitigation of anti-drug antibody development, we are investigating the role of protein aggregates in unwanted immune response towards therapeutic proteins.

Abstract

Therapeutic product immunogenicity is the propensity of a recombinant protein to induce unwanted immune response. An anti-drug antibody (ADA) response can occur upon repeated administration which can limit safety and efficacy. Sustained ADA response against recombinant human acid alpha-glucosidase (rhGAA), used in the treatment of Pompe disease, negatively impacts clinical outcome. Factors of immunogenicity of rhGAA are generally unknown beyond patient status for cross-reactive immunological material. Protein aggregation has gained considerable interest as a factor of therapeutic product immunogenicity. Heterogeneity of aggregates and the wide range of stresses encountered by proteins during bioprocessing render aggregation a complex issue. There is a lack of understanding of the type and size of aggregates universally implicated in therapeutic product immunogenicity. Here, rhGAA is shown to form aggregates which likely carry an immunogenic risk. Identifying factors of immunogenicity of rhGAA in order to develop mitigation strategies will help to improve clinical outcomes.

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