An Advanced Lytic by Design

Genentech's goal in developing TNKase was to create a thrombolytic agent 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 differences between TNKase and rt‑PA. 3 The process of designing TNKase began with a systematic effort to map critical features of the rt‑PA molecule responsible for its clinical properties. 6 Using site‑directed mutagenesis, over 1000 variants of rt‑PA were evaluated, resulting in the identification of key structure‑function relationships. 3 The three targeted alterations which differentiate TNKase from the rt‑PA molecule contribute to the following pharmacological improvements:

  • Increased Fibrin Specificity
    • TNKase has 8-10 times the fibrin selectivity in vitro of Activase® (alteplase) 3 (the clinical significance of increased fibrin specificity has not been established) 6
  • Greater Resistance to Plasminogen Activator Inhibitor-1 (PAI-1) 6
    • TNKase is more resistant to PAI-1 in vitro, relative to Activase. PAI-1 is a natural fibrinolysis inhibitor that can disrupt plasminogen activation
  • Long Plasma Half-Life 6
    • The initial half-life of TNKase is approximately 3 to 6 times that of Activase in vivo, allowing it to be delivered in one single bolus over 5 seconds

The clinical significance of increased fibrin specificity, greater resistance to PAI-1, and long plasma half-life have not been established.

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