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Biosimilars: the process is the product. The example of recombinant streptokinase

BACKGROUND: Worldwide, streptokinase remains the most used thrombolytic agent for the treatment of myocardial infarction. Recombinant streptokinase, from E. coli, is increasingly used in developing countries as a biosimilar of native streptokinase; however, potency assignments relative to the WHO In...

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Autores principales: Thelwell, C, Longstaff, C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241032/
https://www.ncbi.nlm.nih.gov/pubmed/24913658
http://dx.doi.org/10.1111/jth.12629
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author Thelwell, C
Longstaff, C
author_facet Thelwell, C
Longstaff, C
author_sort Thelwell, C
collection PubMed
description BACKGROUND: Worldwide, streptokinase remains the most used thrombolytic agent for the treatment of myocardial infarction. Recombinant streptokinase, from E. coli, is increasingly used in developing countries as a biosimilar of native streptokinase; however, potency assignments relative to the WHO International Standard (IS) are highly variable with potentially dangerous consequences. A proportion of recombinant streptokinase appears to be incompletely processed, retaining the amino-terminal methionine engineered for intracellular expression. OBJECTIVES: To investigate and quantify the impact of an amino-terminal methionine on streptokinase activity. METHODS: Mature native streptokinase (rSK) was cloned and a novel variant constructed to include an amino-terminal methionine (rSK-Met) that is not susceptible to processing during expression. Potencies of rSK and rSK-Met were determined relative to the WHO IS using a chromogenic solution (European Pharmacopoeia) assay, and fibrin-based assays. RESULTS: In the chromogenic solution assay there was no measurable difference between rSK and rSK-Met activities. In the fibrin-based methods, however, potency estimates for rSK-Met were greatly reduced compared with rSK, and fibrinolytic activity for rSK-Met was shown to increase over time with methionine aminopeptidase treatment. This apparent difference in activity and fibrin selectivity was consistent with potency estimates for several different batches of commercial recombinant streptokinase products also tested; consequently, different potencies would be assigned to therapeutic recombinant streptokinase products depending on the degree of amino-terminal methionine processing, and on the pharmacopoeial assay method used, affecting the dosage patients receive. This has serious health implications and provides an example of the danger in the unregulated clinical use of biosimilars.
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spelling pubmed-42410322014-12-08 Biosimilars: the process is the product. The example of recombinant streptokinase Thelwell, C Longstaff, C J Thromb Haemost Cardiovascular Medicine BACKGROUND: Worldwide, streptokinase remains the most used thrombolytic agent for the treatment of myocardial infarction. Recombinant streptokinase, from E. coli, is increasingly used in developing countries as a biosimilar of native streptokinase; however, potency assignments relative to the WHO International Standard (IS) are highly variable with potentially dangerous consequences. A proportion of recombinant streptokinase appears to be incompletely processed, retaining the amino-terminal methionine engineered for intracellular expression. OBJECTIVES: To investigate and quantify the impact of an amino-terminal methionine on streptokinase activity. METHODS: Mature native streptokinase (rSK) was cloned and a novel variant constructed to include an amino-terminal methionine (rSK-Met) that is not susceptible to processing during expression. Potencies of rSK and rSK-Met were determined relative to the WHO IS using a chromogenic solution (European Pharmacopoeia) assay, and fibrin-based assays. RESULTS: In the chromogenic solution assay there was no measurable difference between rSK and rSK-Met activities. In the fibrin-based methods, however, potency estimates for rSK-Met were greatly reduced compared with rSK, and fibrinolytic activity for rSK-Met was shown to increase over time with methionine aminopeptidase treatment. This apparent difference in activity and fibrin selectivity was consistent with potency estimates for several different batches of commercial recombinant streptokinase products also tested; consequently, different potencies would be assigned to therapeutic recombinant streptokinase products depending on the degree of amino-terminal methionine processing, and on the pharmacopoeial assay method used, affecting the dosage patients receive. This has serious health implications and provides an example of the danger in the unregulated clinical use of biosimilars. BlackWell Publishing Ltd 2014-08 2014-07-31 /pmc/articles/PMC4241032/ /pubmed/24913658 http://dx.doi.org/10.1111/jth.12629 Text en © 2014 Crown copyright. Journal of Thrombosis and Haemostasis published by Wiley Periodicals Inc. on behalf of the International Society on Thrombosis and Haemostasis. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Cardiovascular Medicine
Thelwell, C
Longstaff, C
Biosimilars: the process is the product. The example of recombinant streptokinase
title Biosimilars: the process is the product. The example of recombinant streptokinase
title_full Biosimilars: the process is the product. The example of recombinant streptokinase
title_fullStr Biosimilars: the process is the product. The example of recombinant streptokinase
title_full_unstemmed Biosimilars: the process is the product. The example of recombinant streptokinase
title_short Biosimilars: the process is the product. The example of recombinant streptokinase
title_sort biosimilars: the process is the product. the example of recombinant streptokinase
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4241032/
https://www.ncbi.nlm.nih.gov/pubmed/24913658
http://dx.doi.org/10.1111/jth.12629
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