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

Journal of thrombosis and haemostasis : JTH

PubMedID: 24913658

Thelwell C, Longstaff C. Biosimilars: the process is the product. The example of recombinant streptokinase. J Thromb Haemost. 2014;.
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 Pharmacopoeial) 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 to 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. This article is protected by copyright. All rights reserved.