Commentary: Current Perspectives on the Aggregation of Protein Drugs

摘要: Protein drugs have revolutionized the pharmaceutical industry, offering new treatments for serious diseases. Since first recombinant protein drug, Eli Lilly’s Humulin®, was approved 30 years ago (1), grown from esoteric specialty products to a major drug class. Of 20 top selling in USA third quarter of 2012, nine are proteins. Despite these successes, inherent instability molecules remains an impediment their development and safety efficacy. One most types is aggregation, self-association native through covalent and/or non-covalent interactions. aggregates been associated with increased or decreased potency potential immunogenic side effects, which can be life-threatening. In this themed issue AAPS Journal, we assembled research review articles that address aggregation therapeutic The inspired by presentations at 10th Annual Garnet E. Peck Symposium Industrial Pharmacy, held Purdue University West Lafayette, Indiana, on October 11, 2012. At practical level, interest proteins driven need stable formulations robust manufacturing conditions. At symposium, Dr. David Volkin (Dept. Pharmaceutical Chemistry, Kansas) presented series case studies based his recent work issues. cases showed effects excipients albumin fusion (2) IgG2 monoclonal antibodies (mAbs) (3), role infusion bags solubility IgG4 mAbs (4), methods ensure comparability during mAb process (5), empirical phase diagram approach identifying inhibit (6). article special issue, coauthors summarize studies, present overview mechanisms, describe high throughput approaches monitoring stability (7). In developing products, industry makes use accelerated estimate shelf life storage temperature degradation rates measured higher temperatures. This extrapolation usually assumes dependence reaction follows Arrhenius behavior. However, often exhibits non-Arrhenius dependence, even over relatively narrow ranges. Chris Roberts Chemical Biomolecular Engineering, Delaware) group’s mechanisms origins behavior (8,9). he Wei Wang (Pfizer BioTherapeutics) mechanistic insights discuss implications testing (10). Ensuring aggregate-free requires robust, reproducible analytical methods. ideal method would resolve aggregate monomeric species, quantify size concentration, provide low limit detection, all while achieving moderate cost. Current fall short ideal. For example, exclusion chromatography (SEC) assays soluble expensive low-throughput. Gel electrophoresis (e.g., SDS-PAGE) gives somewhat but generally not quantitative. To limitations, Mary Wirth University) her colleagues novel chromatographic materials silica colloidal crystals. These ordered arrays particles plate heights nanometer range, allowing resolution rapid analysis times. using capillary packed crystals pressure-driven flow, group has separated antibody its less than minute baseline (11). results (12). Together, insight into our current understanding aggregation. Gaps fundamental applied technology remain, however, impeding ability monitor biologics. gaps include limited relative importance partial unfolding, interactions, chemical process; lack physical determinants immune response aggregated forms; poor agreement among available determining particularly subvisible range; incomplete stresses formulation variables. We hope theoretical perspectives here will stimulate additional discussion important area.