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Treatment of myocardial infarction using tgf beta antagonists

a technology of myocardial infarction and beta antagonist, which is applied in the direction of antibody medical ingredients, drug compositions, peptides, etc., can solve the problems of non-st segment elevation mi, myocardium may be stunned (reversibly damaged), and the cost of heart disease is projected to exceed $304.6 billion, so as to reduce the adverse effect of myocardial infarction

Inactive Publication Date: 2013-12-12
GENZYME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for reducing the negative effects of myocardial infarction in patients by administering an antagonist of TGF-β. The antagonist can be an antibody or an antibody fragment that specifically binds to TGF-β, a soluble fragment of TGF-β receptor, or an antisense or interfering RNA oligonucleotide. The method can be initiated within 120 hours of the onset of acute myocardial ischemia. The TGF-β antagonist can also include an ACE inhibitor or an angiotensin II receptor antagonist. Overall, the method aims to protect the heart from the damaging effects of TGF-β and promote heart function.

Problems solved by technology

In 2009, heart disease is projected to cost more than $304.6 billion, including health care services, medications, and lost productivity.
Under these conditions, the necrotic zone may be mainly limited to the subendocardium, typically causing non-ST segment elevation MI.
At the edges of the infarct, the myocardium may be stunned (reversibly damaged) and will eventually recover if bloodflow is restored.
However, cell biochemistry and ultrastructure begin to show abnormalities within 20 min.
The infarcted myocardium is especially soft between 4 and 7 days, and is therefore maximally prone to rupturing.

Method used

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  • Treatment of myocardial infarction using tgf beta antagonists
  • Treatment of myocardial infarction using tgf beta antagonists
  • Treatment of myocardial infarction using tgf beta antagonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

Antibody Purification

[0169]Monoclonal antibodies 1D11 and GC 1008 were purified either from culture supernatant or ascites by protein A-Sepharose chromatography (Goding, J Immunol Meth (1976) 42; 17) (Pharmacia Fien Chemicals, Uppsala, Sweden). The binding of the gamma (γ)1 subclass and gamma (γ)4 subclass monoclonal antibodies, 1D11 and GC 1008, to protein A were enhanced by addition of a commercially prepared binding buffer (BioRad, Richmond, Calif.). Antibodies were eluted from the protein A-Sepharose with 0.05 M glycine-HCl plus 0.15 M NaCl buffer (pH 2.3), dialyzed overnight versus PBS and NaCl buffer (pH 2.3), dialyzed overnight versus PBS and stored at −20 degrees Celsius. The gamma (γ) 1 and gamma (γ) 4 subclass antibodies purified from supernatants were concentrated and partially purified by ammonium sulfate precipitation (50% saturated) prior to protein A-chromatography.

example 2

Effect of a TGF-β Inhibitor in a Rat Model of Cardiac Ischemia Reperfusion

[0170]Twelve to fourteen-week-old female Lewis rats were assigned to five treatment groups. At day 0 (D0), all animals underwent a cardiac ischemia followed by reperfusion procedure (I / R). The cardiac ischemia was created by temporarily ligating the left anterior descending coronary artery on the left ventricle of the heart for 60 minutes. The ligation was then released allowing for reperfusion of the ischemic part of the heart. Starting 3 or 5 days post I / R, 5 mg / kg of 1D11 or control article (negative-control antibody 13C4 or vehicle) was administered by intravenous (IV) injection, and then readministered every third day until day 28.

[0171]In order to analyze the area at risk (AAR), 15 μm diameter microspheres labeled with a yellow fluorochrome and were injected into the left ventricle of the heart immediately before releasing the temporary ligation of the left descending coronary artery (D0). The microspher...

example 3

Effect of Timing of Administration of a TGF-β Inhibitor in a Rat Model of Cardiac Ischemia Reperfusion

[0179]The effect of different timing of administration of 1D11, a TGF-β inhibitor antibody, on myocardial fibrosis in a rat model of cardiac ischemia followed by reperfusion (I / R) was observed. 1D11 administration was initiated at either 0, 1 or 5 days after cardiac I / R. The effect of a reduction in myocardial fibrosis resulted in improved heart function as measured by echocardiography.

[0180]Twelve to fourteen week old female Lewis rats were assigned to seven different treatment groups. All animals underwent a cardiac ischemia followed by a reperfusion procedure (I / R). Cardiac ischemia was created by temporarily ligating the left anterior descending coronary artery on the left ventricle of the heart for 60 minutes. The ligation was then released allowing for reperfusion of the ischemic part of the heart, Starting 0 (2 hours post-reperfusion), 1 or 5 days post I / R, 5 mg / kg of 1D11 or...

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Abstract

Disclosed herein is a method of treating a patient suffering a myocardial infarction, particularly an acute myocardial infarction, or of reducing an adverse consequence of a myocardial infarction in a patient comprising administering an antagonist of TGF-β to the patient during the acute stage of the myocardial infarction.

Description

BACKGROUND[0001]1. Field of the Disclosure[0002]This disclosure relates to methods of reducing adverse consequences of myocardial infarction.[0003]2. Description of the Related Art[0004]The problems and health consequences of heart disease are far reaching. Heart disease is the leading cause of death for both women and men in the United States. (Kung H C, Hoyert D L, Xu J, Murphy S L. Deaths: final data for 2005. National Vital Statistics Reports. 2008; 56(10)). Every 34 seconds a person in the United States dies from heart disease. More than 2,500 Americans die from heart disease each day. In 2005, 652,091 people died of heart disease (50.5% of them women). This was 27.1% of all U.S. deaths. Heart disease is the leading cause of death for American Indians and Alaska Natives, blacks, Hispanics, and whites. For Asians and Pacific Islanders, cancer is the leading cause of death (accounting for 27.5% of all deaths), heart disease is a close second (25.0%). (CDC. Deaths: leading causes ...

Claims

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Application Information

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IPC IPC(8): C07K16/22A61K39/395A61K45/06
CPCC07K16/22A61K45/06A61K39/3955A61K2039/505A61P5/00A61P9/10A61P29/00A61P43/00C07K2317/21A61K39/395A61K48/00A61K2121/00A61K2039/545C07K14/495C07K2317/56C07K2317/76G01N33/50
Inventor AKITA, GEOFFREY YGREGORY, RICHARDLONNING, SCOTTKUDEL, AMELIA
Owner GENZYME CORP
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