Page 62 - ITPS-8-2

INNOSC Theranostics and
Pharmacological Sciences Preclinical study of GBpoietin biosimilar

the urine of aplastic anemia patients and characterized as The purpose of this study is to provide a comprehensive
a 34000 Da protein. The expression of this endogenous overview of the preclinical studies conducted on rhEPO,
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glycoprotein is controlled by the transcription factor with a focus on its safety, efficacy, and potential as a drug
hypoxia-inducible factor. Carbohydrates constitute 40% product. As a prelude to clinical trials and subsequent
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of the molecule, primarily in the form of sialic acid, which regulatory approval, preclinical investigations play a
is distributed across three N-linked and one O-linked pivotal role in elucidating the pharmacological properties,
glycosylation sites. These carbohydrates are necessary for toxicological profiles, and mechanisms of action of
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the biological function of EPO. The terminal sialic acid novel therapeutic agents. 16,17 The exploration of rhEPO
residues prevent rapid hepatic clearance, preserving its begins with an examination of the protein’s structure
activity in the bone marrow. Conversely, the biological and the underlying genetic modifications that render it
activity of EPO in vivo is lost when sialic acid is a recombinant biopharmaceutical. By delving into the
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enzymatically removed by neuraminidases. The kidneys molecular intricacies of rhEPO, we aim to establish a
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are the primary physiological site of EPO synthesis, foundational understanding of its design and functionality.
and its production increases in response to a localized In addition, this study will highlight the significance
reduction in renal oxygen supply or systemic anemia. of rhEPO in the context of endogenous EPO while
EPO interacts with its target cells through EPORs on the emphasizing the potential advantages and limitations of
cell surface. The receptor undergoes homodimerization using the recombinant form.
upon EPO binding, activating Janus kinase 2 (JAK2) The first-ever alfa epoetin product, Eprex , is a
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through transphosphorylation. Phosphorylated receptor prescription medication with a track record of safety and
tyrosines recruit intracellular proteins like STAT5, which, effectiveness. Eprex was manufactured by Johnson
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upon activation, enter the nucleus to induce erythroid & Johnson and it was the first EPO formulation to
gene transcription. Phosphatases dephosphorylate receive regulatory approval in Europe in 1988. In the
JAK2 to downregulate the receptor. EPO can bind to the early 1990s, physicians outside of the United States
tissue-protective receptor, specifically EPOR/CD131 adopted the subcutaneous route of administration of
heterodimer, to play a critical role in tissue protection EPO for hemodialysis patients due to the socioeconomic
and immune regulation in addition to its function in benefit for the patients. GBpoietin is a biosimilar of
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erythropoiesis. These receptors are expressed mostly on Eprex , which was developed by Globe Biotech Limited
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erythroid progenitor cells, but they are also present in and synthesized in genetically engineered Chinese
neuronal, endothelial, multipotent hematopoietic, and hamster ovary cells. Upstream and downstream process
embryonic stem cells. 7 development and validation were done for large-scale
As a therapeutic agent, EPO is made using recombinant production. Step-by-step analytical results confirmed the
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DNA technology in mammalian cell cultures that were biosimilarity of GBpoietin to Eprex in terms of molecular
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transfected with the human EPO gene. Recombinant DNA characterization. 21
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technology has enabled the production of recombinant This study investigated the preclinical safety assessments,
human EPO (rhEPO), allowing its extensive therapeutic encompassing acute and chronic toxicity studies in relevant
application in clinical settings. Non-clinical tests should animal models. Comprehensive evaluations of potential
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be conducted following manufacturing changes in a adverse effects, dose-dependent responses, and organ-
biologic product and for products claimed to be similar to specific toxicity are crucial in establishing a safety profile
an already approved one. 10,11 A series of in vitro receptor for rhEPO, guiding subsequent clinical trial designs, and
binding studies and in vivo investigations were required mitigating risks associated with human administration.
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under the guidelines “if there are specific uncertainties This study, designed for the preclinical safety assessment
or concerns regarding safety.” Clinical evidence suggests of GBpoietin , includes the evaluation of single- and
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that rhEPO can be used to treat anemia associated with repeated-dose toxicity. With this goal, the product was
conditions such as chronic renal insufficiencies, rheumatoid compared to a commercial homolog (Eprex ) in Wister
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arthritis, premature birth, chemotherapy, transfusions, and rats to assess the toxicity of GBpoietin .
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hematological diseases. When rhEPO is administered, no
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allergies have been reported; nevertheless, a small number 2. Materials and methods
of patients have had arthralgias and local cutaneous
responses. Preclinical trials involving rhEPO are, 2.1. Materials
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therefore, important for establishing its safety, and efficacy, The drug product, GBpoietin (code name: GBPD002),
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and understanding its potential therapeutic applications was obtained from Globe Biotech Limited (Bangladesh)
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across various medical conditions. 15 while the reference product, Eprex , was purchased from
Volume 8 Issue 2 (2025) 56 doi: 10.36922/itps.5797