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      Physicochemical and biological evaluation of JR-131 as a biosimilar to a long-acting erythropoiesis-stimulating agent darbepoetin alfa

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          Abstract

          Renal anemia is predominantly caused by a relative deficiency in erythropoietin (EPO). Conventional treatment for renal anemia includes the use of recombinant human EPO (rhEPO) or a long-acting erythropoiesis-activating agent named darbepoetin alfa, which is a modified rhEPO with a carbohydrate chain structure that differs from native hEPO. We have developed a biosimilar to darbepoetin alfa designated JR-131. Here, we comprehensively compare the physicochemical and biological characteristics of JR-131 to darbepoetin alfa. JR-131 demonstrated similar protein structure to the originator, darbepoetin alfa, by peptide mapping and circular dichroism spectroscopy. Additionally, mass spectroscopic analyses and capillary zone electrophoresis revealed similar glycosylation patterns between the two products. Human bone marrow-derived erythroblasts differentiated and proliferated to form colonies with JR-131 to a similar degree as darbepoetin alfa. Finally, JR-131 stimulated erythropoiesis and improved anemia in rats similarly to darbepoetin alfa. Our data show the similarity in physicochemical and biological properties of JR-131 to those of darbepoetin alfa, and JR-131 therefore represents a biosimilar for use in the treatment of renal anemia.

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          Most cited references 16

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          Erythropoietin receptor activation by a ligand-induced conformation change.

           I Wilson,  I Remy,  S Michnick (1999)
          Erythropoietin and other cytokine receptors are thought to be activated through hormone-induced dimerization and autophosphorylation of JAK kinases associated with the receptor intracellular domains. An in vivo protein fragment complementation assay was used to obtain evidence for an alternative mechanism in which unliganded erythropoietin receptor dimers exist in a conformation that prevents activation of JAK2 but then undergo a ligand-induced conformation change that allows JAK2 to be activated. These results are consistent with crystallographic evidence of distinct dimeric configurations for unliganded and ligand-bound forms of the erythropoietin receptor.
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            Development and characterization of novel erythropoiesis stimulating protein (NESP)

             J Egrie,  J Browne (2001)
            Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor-binding affinity. These observations led to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity. Hyperglycosylated recombinant human EPO (rHuEPO) analogues were developed to test this hypothesis. Darbepoetin alfa (novel erythropoiesis stimulating protein, NESP, ARANESPTM, Amgen Inc, Thousand Oaks, CA), which was engineered to contain 5 N-linked carbohydrate chains (two more than rHuEPO), has been evaluated in preclinical animal studies. Due to its increased sialic acid-containing carbohydrate content, NESP is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge. Compared with rHuEPO, it has an approximate 3-fold longer serum half-life, greater in vivo potency, and can be administered less frequently to obtain the same biological response. NESP is currently being evaluated in human clinical trials for treatment of anaemia and reduction in its incidence.© 2001 Cance Cance Cancer Research Campaign
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              Renal erythropoietin-producing cells in health and disease

              Erythropoietin (Epo) is an indispensable erythropoietic hormone primarily produced from renal Epo-producing cells (REPs). Epo production in REPs is tightly regulated in a hypoxia-inducible manner to maintain tissue oxygen homeostasis. Insufficient Epo production by REPs causes renal anemia and anemia associated with chronic disorders. Recent studies have broadened our understanding of REPs from prototypic hypoxia-responsive cells to dynamic fibrogenic cells. In chronic kidney disease, REPs are the major source of scar-forming myofibroblasts and actively produce fibrogenic molecules, including inflammatory cytokines. Notably, myofibroblast-transformed REPs (MF-REPs) recover their original physiological properties after resolution of the disease insults, suggesting that renal anemia and fibrosis could be reversible to some extent. Therefore, understanding the plasticity of REPs will lead to the development of novel targeted therapeutics for both renal fibrosis and anemia. This review summarizes the regulatory mechanisms how hypoxia-inducible Epo gene expression is attained in health and disease conditions.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Supervision
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Supervision
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: Supervision
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Supervision
                Role: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 April 2020
                2020
                : 15
                : 4
                Affiliations
                [1 ] Research Division, JCR Pharmaceuticals Co., Ltd., Kobe, Japan
                [2 ] Research Division, Kissei Pharmaceutical Co., Ltd., Azumino, Japan
                [3 ] Research Planning Division, JCR Pharmaceuticals Co., Ltd., Kobe, Japan
                Universitatsklinikum Wurzburg, GERMANY
                Author notes

                Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Junya Tani, Yae Ito, Makoto Yamakami, Tsuyoshi Fukui, Yukichi Hatano, Shinji Kakimoto, Ayaka Kotani, Atsushi Sugimura, Kazutoshi Mihara, Ryuji Yamamoto, Noboru Tanaka, Kohtaro Minami, Kenichi Takahashi, and Tohru Hirato are employees of JCR Pharmaceuticals. Satoshi Tatemichi is an employee of Kissei Pharmaceutical. This study was funded by JCR Pharmaceuticals and Kissei Pharmaceutical. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Article
                PONE-D-19-34327
                10.1371/journal.pone.0231830
                7164597
                32302352
                © 2020 Tani et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 9, Tables: 2, Pages: 17
                Product
                Funding
                This study was sponsored by JCR Pharmaceuticals and Kissei Pharmaceutical. The commercial affiliates provided support in the form of salaries for authors. The specific roles of authors are articulated in the Author Contributions section. The funders had no additional role in the study design, data collection and analysis, or decision to publish.
                Categories
                Research Article
                Medicine and Health Sciences
                Hematology
                Anemia
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Amino Acid Analysis
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Amino Acid Analysis
                Biology and Life Sciences
                Biochemistry
                Proteomics
                Peptide Mapping
                Physical Sciences
                Chemistry
                Chemical Compounds
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Sialic Acids
                Physical Sciences
                Chemistry
                Organic Chemistry
                Organic Compounds
                Carbohydrates
                Monosaccharides
                Sialic Acids
                Biology and Life Sciences
                Molecular Biology
                Macromolecular Structure Analysis
                Protein Structure
                Biology and Life Sciences
                Biochemistry
                Proteins
                Protein Structure
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Sequencing Techniques
                Protein Sequencing
                Research and Analysis Methods
                Molecular Biology Techniques
                Sequencing Techniques
                Protein Sequencing
                Biology and Life Sciences
                Biochemistry
                Proteins
                Recombinant Proteins
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Surgical Excision
                Nephrectomy
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Urinary System Procedures
                Nephrectomy
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

                Uncategorized

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