Abstract
Darren P. Baker, PhD
Darren P. Baker, PhD, passed away suddenly on September 15, 2022, at the age of 57 years. He is survived by his wife, Dr. Patricia Cairns DVM, and their children: Cameron, Jacqueline, and Graeme Baker. He was an active member of the International Cytokine & Interferon Society (ICIS) and its forerunner, the International Society for Interferon & Cytokine Research (ISICR), for many years. His scientific legacy is directly linked to the development and clinical application of pegylated interferon-beta (IFN-β) as a treatment for multiple sclerosis (MS) and other diseases. In this editorial, I wish to highlight some of the key research reports that Darren published during his career regarding the preclinical and clinical development of pegylated IFN-β.
Darren was born on June 9, 1965, in Southampton, England. He received a bachelor of science (BS) degree in microbiology from Swansea University (United Kingdom) in 1986 and a doctor of philosophy (PhD) degree in biochemistry from the University of Glasgow (U.K.) in 1990. The title of his graduate thesis was “Purification and Characterization of D(-)-Mandelate Dehydrogenase from the Yeast Rhodotorula graminis.” The findings derived from his graduate thesis work resulted in several scientific publications (Baker et al., 1992; Basak et al., 1993).
After completing his graduate studies in the United Kingdom, Darren accepted a postdoctoral fellowship in the chemistry department at ETH Zurich (Switzerland). One year later, he moved to Boston, MA (USA), where he continued to develop his research skills in enzyme biochemistry as a junior faculty member in the department of chemistry at Boston College. During this period, his research work focused on purifying and characterizing the aspartate transcarbamoylase enzyme of Escherichia coli (Baker et al., 1995; Baker et al., 1994). His early research work on various microbial enzymes helped him to hone his skills and experience in protein purification and characterization.
In 1995, Darren moved from academia to the biotechnology arena when he joined the drug discovery department at Biogen, Inc., (Cambridge, MA). As a new research scientist at Biogen, the focus of his research activities shifted away from basic microbial enzyme chemistry to a more applied focus on purification and characterization of mammalian proteins, including cytokines such as interleukin-2 (IL-2) and IFN-β. One of the primary research projects that he worked on at Biogen focused on development and application of chemical methods, particularly PEGylation, to extend the in vivo half-life of recombinant IFN-β.
Together with his coworkers at Biogen, he developed several novel pegylated forms of IFN-β and evaluated the pharmacokinetic and pharmacodynamic properties of these modified forms in several different mammalian species, including rats and monkeys (Arduini et al., 2004; Pepinsky et al., 2001). He also evaluated the antitumor activity of pegylated IFN-β against melanoma and several other tumor cell types in various preclinical animal models (Baker et al., 2006; Boccia et al., 2017).
Darren was among the first to recognize the clinical potential of pegylated IFN-β as a more effective form of IFN-β for treatment of patients with relapsing MS (Baker et al., 2010). His pioneering work regarding the development and preclinical testing of pegylated IFN-β led to subsequent exploratory pharmacokinetic studies of peginterferon β-1a in rhesus monkeys (Hu et al., 2011) and humans (Hu et al., 2012). These preclinical and early clinical studies in turn paved the way for the phase 3 clinical trials that ultimately led to the approval of peginterferon β-1a (Plegridy®) in 2014 as a therapeutic agent for treatment of patients with MS (Calabresi et al., 2014; Kieseier et al., 2015).
Unmodified (ie, non-pegylated) IFN-β drug products such as Avonex, Rebif, and Betaseron have a relatively short half-life in vivo. This short half-life necessitates that they be administered at least once per week to achieve efficacy in MS patients. Avonex is normally administered once per week; Rebif is administered 3 times per week, and Betaseron is administered once every other day. To improve the pharmacokinetic properties of IFN-β, PEGylation technology was used to develop modified forms of recombinant human IFN-β such as Plegridy that require less frequent dosing.
Attachment of polyethylene glycol (PEG) significantly increases the hydrodynamic radius of the linked protein. This results in increased bioavailability, longer elimination half-life, and maximal attainable serum concentrations while decreasing renal clearance and the volume of distribution.
PEGylation may also reduce receptor- and antibody-mediated clearance mechanisms and proteolysis of the bioactive protein, IFN-β. It may also decrease antigenicity and immunogenicity of the target protein because the PEG moiety can block recognition of specific epitopes by the immune system. In general, PEGylation also increases solubility and stability of the protein to which it is conjugated. The longer half-life of pegylated IFN-β versus nonpegylated IFN-β allows for less frequent dosing. In addition, the reduced dosing frequency of pegylated IFN-β versus nonpegylated IFN-β correlates with a decrease in the frequency of IFN-β-induced side effects (ie, adverse reactions).
The efficacy of recombinant human IFN-β drug products such as Avonex and Plegridy is mediated by their ability to upregulate expression of a large set of IFN-stimulated genes (ISGs). These ISGs and their corresponding proteins mediate the antiviral, antiproliferative, and immunomodulatory activities that are associated with the therapeutic effects of IFN-β in MS patients. The precise mechanism of action of IFN-β has not been fully established. However, some studies indicate that IFN-β functions in part by upregulating production and activity of endogenous interleukin-10 (IL-10) and other anti-inflammatory cytokines (Porrini et al., 1995; Rudick et al., 1996; Wang et al., 2000).
This issue of JICR features an interesting new study report by Nguyen and coworkers, entitled “Prolonged Interferon-Stimulated Gene and Protein Signatures in Multiple Sclerosis Induced by PEGylated IFN-β-1a Compared to Non-PEGylated IFN-β-1a” (Nguyen et al., 2023). This study was led by Drs. Xuan Feng and Anthony Reder from the department of neurology at the University of Chicago. They compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of MS patients who were treated with either nonpegylated IFN-β (Avonex) or pegylated IFN-β (Plegridy).
Blood samples were collected at several time points, including 0, 6, 24, and 48 h postinjection, after treatment with pegylated IFN-β (Plegridy) or nonpegylated IFN-β (Avonex) for 1 month (short term) or 7 months (long term). Avonex (30 μg) was administered intramuscularly once every 7 days; whereas Plegridy (125 μg) was administered once every 14 days after the first 4 weeks (28 days) of therapy.
The authors found that pegylated and nonpegylated IFN-β induced similar ISG expression profiles; however, the induction of ISGs in PBMCs from patients who were treated with pegylated IFN-β (Plegridy) was more prolonged than in PBMCs from patients treated with nonpegylated IFN-β (Avonex). In addition, the overall magnitude of ISG induction by PBMCs from patients who received pegylated IFN-β for 7 months was significantly higher than in PBMCs from patients who received nonpegylated IFN-β.
In summary, the induction of ISG expression by nonpegylated IFN-β was more rapid but more short lived than the induction of ISG expression by pegylated IFN-β that was slower but more prolonged. The authors observed similar trends when they measured the levels of a corresponding subset of proteins in serum samples from patients who were treated with pegylated versus nonpegylated IFN-β.
The findings described in this new research report by Nguyen et al. are linked to the excellent research and development work that Darren Baker directed during the years he was at Biogen. I believe that Darren would have been very interested in this new study report because it helps to further define the mechanism of action of IFN-β as a treatment for MS. It also increases our understanding of the pharmacokinetic and pharmacodynamic properties of pegylated versus nonpegylated IFN-β.
In 2016, Darren moved from Biogen Idec to Sanofi Genzyme (Cambridge, MA) where he served as director of the biostatistics and medical writing group until his passing in September 2022. During the years he was with Sanofi Genzyme, he continued to help facilitate development and evaluation of novel drugs for MS, including alemtuzumab, an anti-CD52 monoclonal antibody, and teriflunomide (AUBAGIO®). Teriflunomide is an immunomodulatory drug that inhibits pyrimidine synthesis de novo by blocking the enzyme, dihydroorotate dehydrogenase.
Darren first joined the ISICR in 2001, and he continued his membership after ISICR merged with the International Cytokine Society (ICS) to form the current ICIS. During the 20+ years that Darren was an active member of ISICR and ICIS, he developed a number of productive collaborations with other scientists who shared an interest in the biology and biochemistry of type I interferons.
Some of his key academic collaborators included Ana Gamero (Temple University, Philadelphia, PA), Andrew Larner (Virginia Commonwealth University, Richmond, VA), Nancy Reich (Stony Brook University, NY), Eleanor Fish (University of Toronto, Canada), Leon Platanias (Northwestern University, Chicago, IL), Michael David (University of California San Diego, La Jolla, CA), Gideon Schreiber (Weizmann Institute, Rehovot, Israel), and Serge Fuchs (University of Pennsylvania, Philadelphia, PA), among others. He coauthored research reports with every one of these scientists.
Throughout his career, Darren sustained an enthusiastic interest in interferon-related biochemistry and biology. He genuinely enjoyed interacting and collaborating with other scientists on a wide variety of research projects related to type I interferons, especially IFN-β. The pharmaceutical development of IFN-β was supported by the basic research projects that Darren participated in during the years he was at Biogen. These collaborative studies helped to define how type I interferons bind to their cell surface receptors and mediate signal transduction.
During his lifetime, Darren coauthored well over a hundred publications in high quality peer-reviewed scientific journals. The clinical success of pegylated IFN-β as a therapeutic agent for patients with MS is a testament to the pioneering research and development work that Darren spearheaded during the 2 decades he was at Biogen. He had a wonderful sense of humor and will be sadly missed by everyone who knew him. However, I believe his scientific legacy will live on for many years to come.