Structural Identification of Modified Amino Acids on the Interface between EPO and Its Receptor from EPO BRP, Human Recombinant Erythropoietin by LC/MS Analysis

Song, Kwang-Eun; Byeon, Jaehee; Moon, Dae-Bong; Kim, Hyong-Ha; Choi, Yoo-Joo; Suh, Jung Keun

doi:10.14348/molcells.2014.0214

Cited by 11 publications

(13 citation statements)

References 14 publications

(19 reference statements)

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“…Chemical modifications are generated during upstream and downstream processing, formulation, and storage, including oxidation, deamidation, isomerization, glycation, and Gln/Glu cyclization [80]. Those PTMs can affect activity, stability, and immunogenicity and thus must be well-characterized, controlled, and monitored during development processes [20,21,81]. Physicochemical and biological analyses are required for monitoring those PTMs [82][83][84][85][86].…”

Section: Post-translational Modification (Ptm)mentioning

confidence: 99%

“…A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product in terms of safety, purity, and potency (safety and effectiveness) [19]. Structural and clinical similarities are to be proven for the biosimilar authorization.Biopharmaceuticals are highly complex molecules compared to small molecule drugs and should be monitored and controlled during the manufacturing processes for well-characterized products [20][21][22]. The characterization of biopharmaceuticals is challenging, which utilize the state-of-the-art technology to meet the international harmonized guidelines, Q5E and Q6B [23,24].…”

mentioning

confidence: 99%

“…Biopharmaceuticals are highly complex molecules compared to small molecule drugs and should be monitored and controlled during the manufacturing processes for well-characterized products [20][21][22]. The characterization of biopharmaceuticals is challenging, which utilize the state-of-the-art technology to meet the international harmonized guidelines, Q5E and Q6B [23,24].…”

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confidence: 99%

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Characterization of Biopharmaceuticals Focusing on Antibody Therapeutics

Kim¹,

Kang²,

Suh³

2018

Biopharmaceuticals

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Biopharmaceuticals are highly complex molecules and also require high quality for safety and efficacy in human uses. For well-characterized products, the desired level of quality should be monitored and controlled during the manufacturing processes. A series of workflow for analytical characterization should be applied for product quality throughout those processes. In this chapter, several analytical techniques are introduced for assessing characteristics of biopharmaceuticals focusing on monoclonal antibodies (mAbs). Analytical characterization for primary structure was performed by mass spectrometry (MS), and assessment of post-translational modifications (PTMs) was done by conventional approaches. The analytical assessments were also done by multi-attribute method (MAM) approach using mass spectrometer (MS), and the performance of MAM was compared to conventional approaches. on the market results in gaining interest for drug development industry, and biopharmaceuticals are considered as fast growing and promising area for drug development [3][4][5][6].The approval of mAb-related products is dramatically increased in the recent years [6,7]. Over 90 mAb-related products are approved by European Medicines Agency (EMA) and US Food and Drug Administration (FDA). Those can be classified into mAb, Fc-fusion, Fab, antibody-drug conjugate (ADC), bispecific mAb (bsAb), and bispecific T cell engager (BiTE). Among them, mAbs are the major product, consisting of 77% of total. Others represent rest 23% of total, Fc-fusion (12%), ADC (5%), Fab (3%), bsAb (2%), and BiTE (1%), respectively. After the first approval of full-length mAb in 1998, mAbs are major product in the biopharmaceutical industry. This increasing number gives high revenue for pharmaceutical companies, and seven mAb-related products are positioned in top 10 drugs in the world, 2017, including Humira, Enbrel, Rituxan, Remicade, AVASTIN, Herceptin, and Lantus [8].Mylotarg is the first approved ADC in 2000, which combined a mAb targeting leukemic blast cells with a bacterial toxin (calicheamicin) [7,9]. ADC is a complex generated between a mAb and small molecule or a peptide, and mAb gives the selective delivery for targeting of cytotoxic drugs [1,[9][10][11]. Since the first approval, four additional ADC products are approved in Europe and USA. bsAb has two different antigen binding sites recognizing two different epitopes in a single mAb, and this dual specificity gives more specific targeting and higher efficacy [12][13][14]. Currently, three bsAbs are approved by EMA or US FDA. The first bsAb, Removab, was approved in 2009 but voluntarily withdrawn in 2013. Fc-fusion proteins are fusions of the IgG Fc domain with a desired linked protein, enhancing pharmacokinetic properties (serum half-life) and pharmacodynamics properties (ADCC and CDC) [6,15]. Following the first approval of Fc-fusion protein, Enbrel in 1998, eight Fc-fusion proteins are authorized for the marketing in the region of Europe and USA.Biosimilars, known as follow-on biologics, which follow t...

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Section: Post-translational Modification (Ptm)mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Characterization of Biopharmaceuticals Focusing on Antibody Therapeutics

Kim¹,

Kang²,

Suh³

2018

Biopharmaceuticals

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“…Site 1 lies within EPO’s D helix and AB coil, and includes N147 and T44 as residues which hydrogen bond to F93 of the EPOR. Site 2 resides within EPO’s A and C helices, including R14 and R10 residues which promote bonding to EPOR M150 87 . Consistent with this model, mutations at site 1 or 2 residues (e.g., G151A, K45D, N147K) compromise EPO’s binding affinity for the EPOR to <1% of wild-type rhEPO 88 .…”

Section: ] Agonist Activation Of Epor/jak2 Complexesmentioning

confidence: 99%

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

Rainville

Jachimowicz

Wojchowski

2015

Expert Opinion on Therapeutic Targets

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Introduction Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy) and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly and may affect cancer progression. Potential high merit therefore exists for defining new targets for anti-anemia agents within EPO, and EPO receptor (EPOR) regulatory circuits. Areas covered EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases and HIF2a acetylases, each with potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer (together with JAK2), and novel agents that trigger EPOR complex activation also remain attractive to develop (activating antibodies, mimetics, small molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be drugable including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases. Expert Opinion While rhEPO (and biosimilars) presently are important mainstay erythropoiesis-stimulating agents, impetus exists for studies of novel ESAs that fortify HIF2a’s effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects and/or costs.

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“…Glycan is a major structural moiety that has important effects on the pharmacokinetics and pharmacodynamics of EPO analogues such as darbepoetin alfa and epoetin alpha and beta . The structure of glycan in EPO plays an important role in various biological activities.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Characterization of N‐Glycosylation in Darbepoetin Alfa

Lee

Choi²,

Choi³

et al. 2019

Bulletin Korean Chem Soc

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EPO analogues are representative glycoprotein drugs composed of heterogeneous, multiple antennary N‐glycans. NESP® and Aranesp® are hyperglycosylated EPO, marketed under the same international nonproprietary name as darbepoetin alfa. The multiple antennary N‐glycans are a key factor that increases the half‐life of the drug in the body, which is closely related to efficacy. Thus, control of N‐glycosylation is important in providing patients with consistent efficacy. This paper reports on the comprehensive characterization of N‐glycosylation of darbepoetin alfa products. The results of N‐glycan analysis of NESP® and Aranesp® showed difference in the ratio of N‐glycans containing N‐acetyllactosamine and O‐acetylated sialic acid. Although there were some differences, the overall N‐glycan structures and profiles were comparable. In particular, darbepoetin alfa products accounted for the largest proportion of tetra‐sialo N‐glycans, greater than 75%. This study increases understanding of N‐glycan profiles and structural information of darbepoetin alfa.

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Structural Identification of Modified Amino Acids on the Interface between EPO and Its Receptor from EPO BRP, Human Recombinant Erythropoietin by LC/MS Analysis

Cited by 11 publications

References 14 publications

Characterization of Biopharmaceuticals Focusing on Antibody Therapeutics

Characterization of Biopharmaceuticals Focusing on Antibody Therapeutics

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

Comprehensive Characterization of N‐Glycosylation in Darbepoetin Alfa

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