An Advanced Lytic by Design

Genentech's goal in developing TNKase was to create a thrombolytic with refined clinical properties relative to wild-type recombinant tissue plasminogen activator (rt-PA). TNKase incorporates three targeted alterations, each of which contributes to the pharmacological improvements that are seen in TNKase relative to rt-PA.

Unprecedented Mapping

The process of designing TNKase began with a systematic effort to map critical features of the rt-PA molecule responsible for its clinical properties.¹ Using site-directed mutagenesis, researchers evaluated over 1,000 variants of rt-PA, allowing them to identify key structure-function relationships.²

An Advanced Lytic with Refined Properties

Three targeted substitutions differentiate TNKase from the rt-PA molecule and contribute to the following pharmacological improvements:

	Increased Fibrin Specificity1
>	With 14-fold greater fibrin selectivity in vitro than Activase®, TNKase is the most fibrin-specfic lytic agent (the clinical significance of increased fibrin specificity has not been established)

	Greater Resistance to Plasminogen Activator Inhibitor-1 (PAI-1)1
>	TNKase is 80-fold more resistant to PAI-1 in vitro relative to Activase. PAI-1 is a natural inhibitor to fibrinolysis that can disrupt plasminogen activation

	Long Plasma Half-Life2
>	The half-life of TNKase is 5 to 7 times that of Activase in vivo, allowing it to be delivered in one single bolus over 5 seconds
>	With the exception of TNKase, other lytic agents must be administered either as infusions or as multiple injections

1. Bennett WF, Paoni NF, Keyt BA, et al. High resolution analysis of functional determinants on human tissue-type plasminogen activator. J Biol Chem. 1991;266:5191-5201.



2. Cannon CP, McCabe CH, Gibson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction: results of the Thrombolysis Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation. 1997;95:351-356.



3. Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci USA. 1994;91(9):3670-3674.



4. Benedict CR, Refino CJ, Keyt BA, et al. New variant of human tissue plasminogen activator (TPA) with enhanced efficacy and lower incidence of bleeding compared with recombinant human TPA. Circulation. 1995;92(10):3032-3040.

Indication: For use in mortality reduction associated with acute myocardial infarction (AMI). Treatment should be initiated as soon as possible after the onset of AMI symptoms.

Safety Information: TNKase therapy is contraindicated in the following conditions due to an increased risk of bleeding: active internal bleeding, history of cerebrovascular accident, intracranial or intraspinal surgery or trauma within 2 months, intracranial neoplasm, arteriovenous malformation, or aneurysm, known bleeding diathesis, and severe uncontrolled hypertension.

All thrombolytic agents increase the risk of bleeding, including intracranial bleeding, and should be used only in eligible patients. In addition, thrombolytic therapy increases the risk of stroke, including hemorrhagic stroke, particularly in elderly patients. In patients with large ST segment elevation myocardial infarction, physicians should choose either thrombolysis or percutaneous coronary intervention (PCI) as the primary treatment strategy for reperfusion. Rescue PCI or subsequent elective PCI may be performed after administration of thrombolytic therapies if medically appropriate.