Antithrombotic agents

a technology of antithrombotic agents and thrombolytic agents, which is applied in the field of monoclonal antibodies, can solve the problems of shunts and prostheses such as artificial heart valves, affecting the function of shunts and prostheses, so as to reduce inhibit thrombolytic agents, the effect of reducing the required dose of thrombolytic agents

Inactive Publication Date: 2007-09-27
UNIVERSITY OF VERMONT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While efficient clotting limits the loss of blood at an injury site, inappropriate formation of thrombi in veins or arteries is a common cause of disability and death.
The formation of clots on foreign surfaces of artificial organs, shunts and prostheses such as artificial heart valves is also problematic.
However, due to their potency, heparin and LMW heparin suffer drawbacks.
Further, the therapeutic target range to achieve the desired level of efficacy without placing the patient at risk for bleeding is narrow.
The optimal strategy for treatment of acute MI remains elusive and available agents and treatment protocols display both negative and positive characteristics.
Further, antiplatelet agents may be accompanied by bleeding or thrombocytopenia.
Also, numerous clinical trials have shown that high doses of thrombolytic agents lead to significant alteration in plasma hemostatic markers.
Although increasing concentrations of tPA lead to enhanced clot dissolution, the alteration in these hemostatic markers mirrors increased liabilities of thrombolytic therapy, particularly the incidence of severe bleeding.

Method used

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Examples

Experimental program
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example 1

Preparation and Screening of Anti-Factor IX Monoclonal Antibodies

[0120] Female Balb / C mice were injected with human factor IX purified as described in Jenny, R. et al., Prep Biochem, 16, 227-245 (1986). Typically, each mouse received an initial injection of 100 ug protein dissolved in 0.15 mL phosphate-buffered saline (PBS) and mixed with 0.15 mL complete Freund's adjuvant. Booster immunizations of 50 ug protein in 0.15 mL PBS with 0.15 mL incomplete Freund's adjuvant were given approximately biweekly over a 2-3 month period. After the final boost, the mouse received 50 ug of Factor IX in PBS three days before spleen / myeloma cell fusions. Spleen cells were isolated from an immunized mouse and fused with NS-1 myeloma cells (Kohler, G. et al., Eur J Immunol, 6, 292-295 (1976)) using polyethylene glycol as described by Oi, V. T. et al. in “Selected Methods in Cellular Immunology,” Mishell, B. B. and Shigii, S. M., eds., Freeman Press, San Francisco. Following the fusion, the cells wer...

example 2

Self-Limiting Effect of Anti-Coagulation Factor Antibodies in Coagulation

[0123] The effect of increasing concentrations of anti-coagulation factor antibodies on activated partial thromboplastin time (aPTT) of human plasma was determined in a fibrometer (Becton-Dickinson Microbiology Systems, Cockeysville, Md.) using Baxter reference procedure LIB0293-J, 3 / 93 revision (Baxter Scientific, Edison, N.J.).

[0124] Prior to the start of the experiment, 2 to 3 mL of 0.02 M CaCl2 in a 5 mL tube were placed into the heating chamber of the fibrometer. Human plasma samples were either freshly drawn and kept on ice or reconstituted per the manufacturer's recommendation from Hemostasis Reference Plasma (American Diagnostics, Greenwich, Conn.).

[0125] Unfractionated heparin from porcine intestinal mucosa (Sigma Chemical, St. Louis, Mo.), low molecular weight heparin from porcine intestinal mucosa (Lovenox®, enoxaparin sodium, Rhone-Poulenc Rorer Pharmaceuticals, Collegeville, Pa.) or mAb anticoag...

example 3

Efficacy of murine Factor IX mAbs in Rat Thrombus Model

[0133] In order to evaluate the efficacy of anti-Factor IX antibodies in prevention of arterial thrombosis, the rat carotid artery thrombosis model as reported by Schumacher et al. in J Cardio Pharm, 22, 526-533 (1993) was adapted. This model consists of segmental injury to the carotid endothelium by oxygen radicals generated by FeCl3 solution applied on the surface of the carotid artery.

[0134] In brief, rats were anesthetized with pentobarbitone sodium, the jugular vein cannulated for intravenous injections and the left femoral artery cannulated for blood pressure and heart rate monitoring. The carotid artery was isolated by aseptic technique via a surgical incision in the neck and equipped with a magnetic flow probe for blood flow measurement. After a period of stabilization, baseline parameters were established for the following variables: carotid blood flow, arterial pressure, heart rate, activated partial thromboplastin t...

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Abstract

Monoclonal antibodies directed against coagulation factors and their use in inhibiting thrombosis in combination with plasminogen activators are disclosed.

Description

FIELD OF THE INVENTION [0001] This invention relates to monoclonal antibodies (mabs) that bind to a human coagulation factor or cofactor and their use as self-limiting inhibitors of thrombosis in combination with plasminogen activators. BACKGROUND OF THE INVENTION [0002] Under normal circumstances, an injury, be it minor or major, to vascular endothelial cells lining a blood vessel triggers a hemostatic response through a sequence of events commonly referred to as the coagulation “cascade.” The cascade culminates in the conversion of soluble fibrinogen to insoluble fibrin which, together with platelets, forms a localized clot or thrombus which prevents extravasation of blood components. Wound healing can then occur followed by clot dissolution and restoration of blood vessel integrity and flow. [0003] The events which occur between injury and clot formation are a carefully regulated and linked series of reactions. In brief, a number of plasma coagulation proteins in inactive proenzy...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K31/00C12N15/02A61K38/00A61P7/00A61P7/02C07H21/04C07K16/00C07K16/10C07K16/36C07K16/40C07K16/46C12N5/06C12N5/10C12N5/12C12N15/09C12P21/02C12P21/08
CPCA61K38/00A61K39/395A61K2039/505C07K16/36C07K16/40C07K2317/92C07K2316/96C07K2317/24A61K2300/00C07K2317/76A61P7/00A61P7/02
Inventor BLACKBURN, MICHAEL NEALFEUERSTEIN, GIORA ZEEVPATEL, ARUNBHAI HARIBHAI
Owner UNIVERSITY OF VERMONT
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