Editorial

Abstract

It is my pleasure to announce that M. Jack Borrok, Neil Mody, Xiaojun Lu, Megan L. Kuhn, Herren Wu, William F. Dall'Acqua, and Ping Tsui were selected to receive the 2018 Ebert Prize. The Ebert Prize is presented annually by the American Pharmacists Association (APhA) Academy of Pharmaceutical Research and Science (APRS) to the authors of an article published in the Journal of Pharmaceutical Sciences (JPharmSci®), which describes particularly new, original, and novel findings that have a high probability of significantly impacting the pharmaceutical sciences. The Ebert Prize was established in 1873, and it is the oldest pharmacy award in existence in the United States. The award consists of a silver medallion bearing the likeness of Albert Ethelbert Ebert who was a former APhA President (Fig. 1). The 2018 Ebert Prize was presented to Dr. Borrok and his coauthors for their outstanding article entitled An “Fc-Silenced” IgG1 Format with Extended Half-Life Designed for Improved Stability (J. Pharm. Sci.,106 (4), 1008-1017, 2017). In this article, the authors describe the biology and consequences on antibody biochemical and biophysical stability when 2 sets of mutations, both residing in the CH2 domain of the Fc (TM and YTE), are combined in one antibody. It had previously been reported that the TM-YTE IgG1 backbone causes a ∼12°C reduction in Tm1 and an increased protein decay coefficient. In this article, the authors confirm the destabilizing effects of TM-YTE on thermostability by differential scanning calorimetry (DSC) and differential scanning fluorimetry (DSF). Furthermore, they show that TM-YTE has increased conformational flexibility by hydrogen/deuterium exchange (HDX) as well as reduced colloidal stability and an increased aggregation rate when compared with the parental IgG. The authors then go on to engineer an improved set of mutations with the same biological properties of TM-YTE but with improved stability profiles. To accomplish this, they dissected the effects of individual mutations within TM on thermostability by identifying the most destabilizing mutations and replacing them with more stable alternatives. The result is an antibody format with extended in vivo half-life and reduced effector binding with enhanced stability compared to the original mutation combination. The members of the 2018 Ebert Prize Selection Committee considered the scientific findings described in this article to be exceptionally novel and very highly significant and impactful. The committee felt that the impact of the findings described in this article would be very far reaching. For example, by using engineering approaches and similar methodologies, pharmaceutical scientists should be able to improve the discovery and development of other antibodies containing Fc mutations while retaining tailored biological activities. The overall impact of this approach will be safer and more efficacious antibodies to treat human diseases. Finally, it should be noted that this article was very highly recommended to JPharmSci®’s Editorial Team by the 2018 Ebert Prize Selection Committee which included Gregory E. Amidon, University of Michigan; Arvind Bansal, National Institute of Pharmaceutical Education and Research; Jared S. Bee, MacroGenics; Christel A. Bergström, Uppsala University; Ben Boyd, Monash University; Mino Caira, University of Capetown; Carla Caramella, University of Pavia; Yoshiharu Deguchi, Teikyo University; Roberto DePaz, REGENXBIO, Inc.; Anastasia Foppoli, Università degli Studi di Milano; Yukio Kato, Kanazawa University; Filippos Kesisoglou, Merck & Company, Inc.; Peter Kleinebudde, Heinrich-Heine-Universität; Hiroyuki Kusuhara, The University of Tokyo; William Lambert, Omeros Corporation; Alessandra Maroni, Universitá degli Studi di Milano; Michael Maurin, Maurin Healthcare Consulting; Miki Nakajima, Kanazawa University; Linda Owers Narhi, Amgen, Inc.; Sumio Ohtsuki, Kumamoto University; Hitoshi Sasaki, Nagasaki University Hospital; Robert Strickley, Nucleo Life Sciences; Changquan Calvin Sun, University of Minnesota; Masanori Tachikawa, Tohoku University; Masatoshi Tomi, Keio University; Susumu Uchiyama, Osaka University; Hiroaki Yuasa, Nagoya City University; and Lucia Zema, Universitá degli Studi di Milano. I would like to take this opportunity to thank these individuals for serving on the 2018 Ebert Prize Selection Committee and for their service on the JPharmSci® Editorial Advisory Board. I would also like to take this opportunity to thank Dr. Borrok and his coauthors for selecting JPharmSci® as the repository for their most original and most significant scientific findings. An “Fc-Silenced” IgG1 Format With Extended Half-Life Designed for Improved StabilityJournal of Pharmaceutical SciencesVol. 106Issue 4PreviewMultiple mutation combinations in the IgG Fc have been characterized to tailor immune effector function or IgG serum persistence to fit desired biological outcomes for monoclonal antibody therapeutics. An unintended consequence of introducing mutations in the Fc (particularly the CH2 domain) can be a reduction in biophysical stability which can correlate with increased aggregation propensity, poor manufacturability, and lower solubility. Herein, we characterize the changes in IgG conformational and colloidal stability when 2 sets of CH2 mutations “TM” (L234F/L235E/P331S) and “YTE” (M252Y/S254T/T256E) are combined to generate an antibody format lacking immune receptor binding and exhibiting extended half-life. Full-Text PDF