Novel inhibitor of hepatocyte growth factor activator for use in modulation of angiogenesis and cardiovascularization

Abstract

Compositions and methods are disclosed for stimulating or inhibiting angiogenesis and/or cardiovascularization in mammals, including humans. Pharmaceutical compositions are based on polypeptides or antagonists thereto that have been identified for one or more of these uses. Disorders that can be diagnosed, prevented, or treated by the compositions herein include trauma such as wounds, various cancers, and disorders of the vessels including atherosclerosis and cardiac hypertrophy. In addition, the present invention is directed to novel polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Description

[0001] This is a continuation of non-provisional application Ser. No. 09 / 742,201 filed Dec. 19, 2000, which is a non-provisional application claiming benefit of provisional application No. 60 / 253,665 filed Nov. 28, 2000, International application No. PCT / US00 / 03565 filed Feb. 11, 2000, and International application No. PCT / US00 / 06884 filed Mar. 15, 2000, which applications are incorporated herein in their entirety by reference.[0002] The present invention relates to compositions and methods useful for promoting or inhibiting angiogenesis and / or cardiovascularization in mammals in need of such biological effect. This includes the diagnosis and treatment of cardiovascular disorders as well as oncological disorders.DESCRIPTION OF BACKGROUND[0003] A. Cardiac Disorders and Factors[0004] Heart failure affects approximately five million Americans, and new cases of heart failure number about 400,000 each year. It is the single most frequent cause of hospitalization for people age 65 and old...

AI Technical Summary

Problems solved by technology

CHF is a syndrome characterized by left ventricular dysfunction, reduced exercise tolerance, impaired quality of life, and markedly shortened life expectancy.

The sine qua non of heart failure is an inability of the heart to pump blood at a rate sufficient to meet the metabolic needs of the body's tissues (in other words, there is insufficient cardiac output).

As noted below, angiotensin II may also have directly deleterious effects on the heart by promoting myocyte necrosis (impairing systolic function) and intracardiac fibrosis (impairing diastolic and in some cases systolic function).

With severe, long-standing overload, however, the hypertrophied cells begin to deteriorate and die.

Cardiac hypertrophy is a significant risk factor for both mortality and morbidity in the clinical course of heart failure.

However, because of its potent vasodilating properties, nifedipine may be harmful, especially in patients with outflow obstruction.

In many patients, however, the initial benefits decrease with time.

However, all positive inotropic agents except digoxigenin have been found to result in increased long-term mortality, in spite of short-term improvements in cardiac performance.

Another treatment modality is heart transplantation, but this is limited by the availability of donor hearts.

However, despite proven efficacy, response to ACE inhibitors has been limited.

For example, while prolonging survival in the setting of heart failure, ACE inhibitors appear to slow the progression towards end-stage heart failure, and substantial numbers of patients on ACE inhibitors have functional class III heart failure.

Moreover, improvement of functional capacity and exercise time is only small and mortality, although reduced, continues to be high.

Hence, ACE inhibitors consistently appear unable to relieve symptoms in more than 60% of heart failure patients and reduce mortality of heart failure only by approximately 15-20%.

However, when the aorta is constricted in these animals (a model of hypertensive cardiac stress), the hearts still become hypertrophic.

ACE inhibitors would presumably not be able to inhibit these pathways.

Cells subjected to long-standing hypertrophy show more obvious disruptions in cellular organization, including markedly enlarged nuclei with highly lobulated membranes, which displace adjacent myofibrils and cause breakdown of normal Z-band registration.

As CHF progresses, structural and hemodynamic damages occur.

While these damages have a variety of manifestations, one characteristic symptom is ventricular hypertrophy.

Myocardial infarction is known to cause both a change in hemodynamic effects and an alteration in structure in the damaged and healthy zones of the heart.

A characteristic of the ventricle that becomes hypertrophic as a result of chronic pressure overload is an impaired diastolic performance.

However, there is no close parallelism between blood pressure levels and cardiac hypertrophy.

Untreated aortic stenosis may lead to increased intracardiac pressure resulting in myocardial hypertrophy and eventually heart failure and death.

Defects such as the narrowing of the valve stenosis or the defective closing of the valve result in an accumulation of blood in the heart cavity or regurgitation of blood past the valve.

If uncorrected, prolonged valvular stenosis or insufficiency may result in cardiac hypertrophy and associated damage to the heart muscle, which may eventually necessitate valve replacement.

Moreover, it is also recognized that, in some cases, cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species.

However, the variability is not evenly distributed throughout the variable domains of antibodies.

However, the measurement of tumor size is very inaccurate.

It is noted, however, that necrosis and inflammatory responses following treatment may actually result in an increase in tumor size, at least initially.

These tumors are usually not amenable to surgery, primarily because of the anatomy of the feline oral cavity.

At present, there is no effective treatment for this tumor.

The tongue can become paralyzed as a result of such tumor, and even if the treatment kills the tumor, the animals may not be able to feed themselves.

However, the use of this model is limited by the rare occurrence of this type of tumor in animals.

Elevated pressure may result from or result in impaired endothelial function and / or vascular disease.

The result is impaired local lymph drainage.

Age-related macular degeneration (AMD) is a leading cause of severe visual loss in the elderly population.

When encapsulated proteins remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37.degree. C., resulting in a loss of biological activity and possible changes in immunogenicity.

When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37.degree. C., resulting in a loss of biological activity and possible changes in immunogenicity.

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