A Bioinformatics Practicum to Develop Student Understanding of Immunological Rejection of Protein Drugs

By O'Donnell, Lauren A.; Meng, Wilson S. et al. | American Journal of Pharmaceutical Education, November 2016 | Go to article overview

A Bioinformatics Practicum to Develop Student Understanding of Immunological Rejection of Protein Drugs


O'Donnell, Lauren A., Meng, Wilson S., Andrick, Benjamin J., Borello, Alexa M., American Journal of Pharmaceutical Education


INTRODUCTION

New protein drugs, including monoclonal antibodies and other recombinant proteins, are being approved for treating a variety of disease states. In 2015 alone, the Food and Drug Administration approved protein drug therapies for treating a variety of conditions, including asthma, plaque psoriasis, high cholesterol, high-risk neuroblastoma, and multiple myeloma as examples. (1) Immunosuppressant protein drugs (eg, etanercept, infliximab) represent 3 of the top 10 revenue-generating drugs in the United States in the past year. (2) As protein drugs become increasingly common in the marketplace and are applied to a wider variety of disease states, there will be an increased need for pharmacists to have an understanding of the factors that may contribute to the success or failure of protein drug therapy. Although many variables may contribute to treatment failure with protein drugs, one known cause is the development of anti-drug antibodies (ADAs). Protein drugs have the potential to be recognized by the immune system, despite quality control efforts to minimize immunogenicity through engineering of amino acid sequences that would be less likely to be immunoreactive. ADAs may then lead to neutralization of the protein drug by the immune system, and thus reduce efficacy or safety. In a cohort of rheumatoid arthritis patients treated with infliximab, an anti-tumor necrosis factor (TNF) monoclonal antibody, Wolbink and colleagues observed that 69% of nonresponding patients had developed ADAs against the drug while only 36% of responding patients had developed ADAs. (3) The presence of ADAs is associated with low plasma concentrations of the drug, which is a negative indicator for therapeutic outcomes. (4) Although it is not yet possible to predict which patients are most likely to mount an immune response against a protein drug, analyzing the potential genetic and environmental factors that contribute to immune recognition and ADA development against this drug class will be important.

Pharmacy students often struggle to understand complex immunological processes and the application of those processes to clinical problems. In order for students to dissect the role of the immune system in interactions with protein drugs, the students require an understanding of how proteins are processed and "viewed" by the immune system. In particular, the role of the major histocompatibility complexes (MHC) is often difficult for students to master. These molecules, also referred to as human leukocyte antigens (HLA molecules) in humans, are responsible for presenting fragments of foreign proteins for recognition by immune cells. The complexity and diversity of MHC alleles dictates whether individuals will respond to an exogenous protein, such as a protein drug, as foreign. MHC genes are characterized by substantial polymorphism (there are approximately 2000 known alleles), with certain genotypes appearing more often in specific populations or in association with particular disease states. In the case of ADAs, MHC Type II (MHC-II) alleles are especially significant in determining whether antigen-presenting cells (eg, dendritic cells, macrophages, B cells) will present epitopes from the protein drug to helper T cells, subsequently leading to antibody production. Briefly, foreign proteins are engulfed by antigen-presenting cells and broken down into peptide fragments in the acidic environment of the phagolysosome. Upon fusion of the phagolysosome and endosome, the peptide fragments from the foreign protein can be loaded onto the MHC-II molecules. The loaded MHC-II molecules are then transported to the surface of the antigen-presenting cell, where the peptide/MHC-II complex is displayed to naive helper T cells. If the helper T cell recognizes and binds to the peptide/MHC-II complex, the helper T cell subsequently activates other immune cells, including the activation of B cells to produce antibodies against the foreign protein. …

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A Bioinformatics Practicum to Develop Student Understanding of Immunological Rejection of Protein Drugs
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