Methods and compositions for the reduction of neutrophil influx and for the treatment of bronchpulmonary dysplasia, respiratory distress syndrome, chronic lung disease, pulmonary fibrosis, asthma and chronic obstructive pulmonary disease

Abstract

The present invention relates generally to the use of recombinant human CC10 (rhCC10), also known as recombinant human uteroglobin, for use as a therapeutic in the treatment of Respiratory Distress Syndrome (RDS), Bronchopulmonary dysplasia (BPD), chronic lung disease and / or pulmonary fibrosis, Asthma and Chronic Obstructive Pulmonary Disease (COPD). More particularly, the invention provides methods, including broadly the critical dosage ranges of rhCC10, which may be administered to safely and effectively treat the aforementioned conditions. The invention further provides a composition useful in administering rhCC10 to humans.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of pending application Ser. No. 11 / 189,229, filed Jul. 25, 2005, which is a continuation-in-part of application Ser. No. 09 / 835,784, filed Apr. 13, 2001, now abandoned, which is a continuation-in-part of application Ser. No. 09 / 549,926, filed Apr. 14, 2000, now abandoned, which is a continuation-in-part of application Ser. No. 09 / 120,264, filed Jul. 21, 1998, now abandoned, which is a continuation-in-part of application Ser. No. 09 / 087,210, filed May 28, 1998, now abandoned, which is a continuation-in-part of application Ser. No. 08 / 864,357, filed May 28, 1997, U.S. Pat. No. 6,255,281. Each of the aforementioned applications and patent are incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates to methods of reducing the influx of neutrophils into the lungs of a human. More specifically the present invention relates to methods of treating r...

AI Technical Summary

Benefits of technology

[0023] It is a further object of the invention to treat, cure or prevent RDS, BDP, chronic lung disease and / or pulmonary fibrosis, asthma, and COPD in humans by reducing total cell counts, neutrophil counts, total protein concentration IL-6 levels and / or IL-8 levels in the serum or tracheal fluid, and therefore the lungs, of patients.

[0024] It is a further object of the invention to provide a safe, well-tolerated and effective dosage range which accomplishes the above objectives and does not significantly inhibit platelet aggregation, suppress the immune response or increase the frequency or severity of adverse events.

[0028] These and other objects, features and advantages are also achieved by administering rhCC10 such that it does not inhibit platelet aggregation, suppress the immune response or increase the frequency or severity of adverse events.

Problems solved by technology

The influx of neutrophils into the lung is known to be a cause of the destruction of functional lung tissue and the harmful symptoms of RDS, BPD, chronic lung disease, pulmonary fibrosis, asthma and COPD.

In RDS, BPD, chronic lung disease and / or pulmonary fibrosis, asthma and COPD total cell influx and neutrophil influx results in damage to and destruction of pulmonary tissue, ultimately causing functional lung tissue to be replaced with non-functioning fibrotic tissue.

Thus, neutrophil influx is ultimately responsible for causing pulmonary fibrosis to the lungs, which lead to damaged lung tissue and possibly death.

These, and other, powerful non-specific destructive mediators released by neutrophils damage all cell types and destroy lung tissue, including breaking down the bronchiolar and alveolar structure, resulting in decreased lung function and respiratory distress.

Local vascular structure is also damaged, resulting in increased vascular permeability and leakage of serum proteins into the lung and tracheal fluid, further impairing function.

This non-specific neutrophil response results in greater damage to respiratory tissue than the original irritant or infectious agent.

BPD and RDS are associated with substantial morbidity and mortality as well as extremely high health care costs.

Still further it is known that higher levels of fibronectin are present in the tracheal fluid and lungs of patients suffering from RDS and BPD and thus it causes and contributes to respiratory distress.

This makes it difficult for the air to move in and out.

This narrowing or obstruction causes the symptoms of asthma.

COPD is a lung disease in which the lungs are damaged, making it hard to breathe.

In COPD, the airways are partly obstructed, making it difficult to get air in and out of the lungs.

They cause the airways to become inflamed and narrowed, and they destroy the elastic fibers that allow the lung to stretch and then return to its resting shape.

This makes breathing air in and out of the lungs more difficult.

People with antitrypsin deficiency have low levels of alpha 1 antitrypsin; the resulting imbalance of proteins leads to the destruction of the lungs and COPD.

However, they are not completely safe to use.

There are dangerous, often life-threatening side effects associated with the use of glucocorticoids in infants, children and adults.

In children, normal growth is stunted, resulting in small stature, due to treatment with corticosteroids.

And in adults, cardiovascular complications, including hypertension and stroke, are major side effects of corticosteroids.

In all patients, corticosteroids lower the patient's immune function and leave them susceptible to infection of all types (bacterial, viral, fungal, etc.), sometimes resulting in a lethal infection.

It is a significant challenge to find an anti-inflammatory agent powerful enough to alleviate respiratory symptoms and which is safe to use.

These infants are not yet able to produce enough natural CC10 on their own, and develop severe lung inflammation.

First, rhCC10 of sufficient purity has not been previously available.

Furthermore, CC10 is known to inhibit platelet aggregation, thus negatively impacting the ability of the blood to clot.

CC10 is also known to suppress the immune system, which could lead to adverse patient consequences, render recipients more susceptible to infection, and prohibit its use in humans, including premature infants.

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