Ralph N Pannell

US Patent:

7837992, Nov 23, 2010

Filed:

Apr 4, 2007

Appl. No.:

11/732620

Inventors:

Victor Gurewich - Cambridge MA, US
Ralph Pannell - Brighton MA, US

Assignee:

Beth Israel Deaconess Medical Center - Boston MA

International Classification:

A61K 38/48
C12N 9/72
C12N 9/68

US Classification:

424 9464, 435215, 435217

Abstract:

A mutant prourokinase plasminogen activator (M5) was developed to make prouPA less subject to spontaneous activation during fibrinolysis. C1-inhibitor complexes with tcM5. The effect of C1-inhibitor on fibrinolysis and fibrinogenolysis by M5 was determined. Supplemental C1-inhibitor restores the stability of M5 but not that of prouPA. Clot lysis by M5 with supplemental C1-inhibitor showed no attenuation of the rate of fibrinolysis, whereas fibrinogenolysis was prevented by C1-inhibitor. Due to higher dose tolerance of M5 with C1-inhibitor, the rate of fibrin-specific lysis reached that achievable by nonspecific fibrinolysis without inhibitor. Plasma C1-inhibitor stabilized M5 in plasma by inhibiting tcM5 and thereby non-specific plasminogen activation. At the same time, fibrin-specific plasminogen activation remained unimpaired. This unusual dissociation of effects has significant implications for improving the safety and efficacy of fibrinolysis.

US Patent:

8187592, May 29, 2012

Filed:

Nov 16, 2010

Appl. No.:

12/947573

Inventors:

Victor Gurewich - Cambridge MA, US
Ralph Pannell - Brighton MA, US

Assignee:

Thrombolytic Science, LLC - Cambridge MA

International Classification:

C12N 9/72
C12N 9/68
A61K 38/48

US Classification:

424 9464, 435415, 435417

Abstract:

A mutant prourokinase plasminogen activator (M5) was developed to make prouPA less subject to spontaneous activation during fibrinolysis. C1-inhibitor complexes with tcM5. The effect of C1-inhibitor on fibrinolysis and fibrinogenolysis by M5 was determined. Supplemental C1-inhibitor restores the stability of M5 but not that of prouPA. Clot lysis by M5 with supplemental C1-inhibitor showed no attenuation of the rate of fibrinolysis, whereas fibrinogenolysis was prevented by C1-inhibitor. Due to higher dose tolerance of M5 with C1-inhibitor, the rate of fibrin-specific lysis reached that achievable by nonspecific fibrinolysis without inhibitor. Plasma C1-inhibitor stabilized M5 in plasma by inhibiting tcM5 and thereby non-specific plasminogen activation. At the same time, fibrin-specific plasminogen activation remained unimpaired. This unusual dissociation of effects has significant implications for improving the safety and efficacy of fibrinolysis.

US Patent:

20090010916, Jan 8, 2009

Filed:

Jul 1, 2008

Appl. No.:

12/215966

Inventors:

Victor Gurewich - Cambridge MA, US
Ralph Pannell - Brighton MA, US

International Classification:

A61K 38/49
A61P 7/00

US Classification:

424 9463

Abstract:

A mutant prourokinase plasminogen activator (M5) was developed to make prouPA less subject to spontaneous conversion to tcuPA in blood at therapeutic concentrations. Two-chain M5 was shown to form complexes with C1-inhibitor, which was the principal inhibitor of tcM5 in plasma. The effect of supplemental additions of C1-inhibitor on fibrinolysis and fibrinogenolysis by M5 was determined. Supplemental C1-inhibitor restored the stability of high-dose M5 and prevented fibrinogenolysis but not fibrinolysis, the rate of which was not compromised by the inhibitor. Due to higher dose tolerance of M5 in the presence of supplemental C1-inhibitor, the rate of fibrin-specific lysis reached that achievable by nonspecific fibrinolysis, which is the maximum possible for a plasminogen activator. Plasma C1-inhibitor stabilized M5 in plasma by inhibiting tcM5 which would otherwise greatly amplify non-specific plasminogen activation causing more tcM5 generation from M5. This unusual dissociation of inhibitory effects, whereby fibrinogenolysis and not fibrinolysis is inhibited, has significant implications for improving the safety and efficacy of fibrinolysis. Methods of reducing bleeding and non-specific plasminogen activation during fibrinolysis by administering M5 along with exogenous C1-inhibitor are disclosed.