Title:  Pulmonary administration of soluble complement receptor-1 (sCR1) and its derivatives

United States Patent:  6,169,068

Assignee:  Avant Immunotherpeutics, Inc. (Needham, MA); Regents of the University of Minnesota (Minneapolis, MN)

Filed:  August 11, 1995

PCT NO:  PCT/US94/01405

102(e) Date:  August 11, 1995

PCT PUB. Date:  August 18, 1994

A method is disclosed for treating diseases or disorders involving complement by pulmonary administration of complement inhibitory proteins such as soluble complement receptor type 1 (sCR1). The present invention relates to the direct treatment of certain complement related disorders by administering complement inhibitory proteins via the pulmonary route, in particular, by direct delivery to the lungs by aerosolization of a complement inhibitory protein and subsequent inhalation.

SUMMARY OF THE INVENTION

The present invention relates to pulmonary administration of a complement inhibitory protein by inhalation for the therapeutic treatment of diseases or disorders involving complement. More particularly, the invention is directed to pulmonary administration of complement receptor 1 (CR1) by inhalation. Thus, the present invention provides an aerosol formulation comprising an amount of a complement inhibitory protein, and more particularly a CR1 protein, effective to inhibit complement and a dispersant. In one embodiment, the complement inhibitory protein, or more particularly, the CR1 protein, can be provided in a liquid aerosol formulation. Alternatively, the complement inhibitory protein, or more particularly, the CR1 protein, can be provided as a dry powder aerosol formulation. In a preferred embodiment, the CR1 is soluble CR1 (sCR1).

The term "complement inhibitory protein" as used herein includes fragments, derivatives and analogs of such complement inhibitory proteins as are known in the art, provided such fragments, derivatives or analogs have complement inhibitory activity.

Furthermore, the present invention is directed to a method for treating a systemic disease or disorder involving complement comprising pulmonary administration of an amount of a complement inhibitory protein effective to inhibit systemic complement activity to a subject suffering from a disease or disorder involving complement. The present invention further provides a method for treating a lung disease or lung disorder involving complement comprising pulmonary administration of an amount of a complement inhibitory protein effective to inhibit complement activity to a subject suffering from the lung disease or lung disorder involving complement.

The present invention further provides a method for treating anaphylaxis comprising administering an amount of a complement inhibitory protein effective to inhibit complement activity to a subject suffering anaphylaxis. In one embodiment, the administration of the complement inhibitory protein can be parenteral. More preferably, the administration of the complement inhibitory protein can be pulmonary. Pulmonary administration is particularly indicated for treatment of bronchoconstriction associated with anaphylaxis.

The present invention still further provides a method for treating bronchoconstriction comprising administering an amount of a complement inhibitory protein effective to inhibit complement activity to a subject suffering bronchoconstriction. In one embodiment, the administration of the complement inhibitory protein can be parenteral. More preferably, the administration of the complement inhibitory protein can be pulmonary. Pulmonary administration is particularly indicated for treatment of bronchoconstriction associated with anaphylaxis, asthma, or other lung irritation or insult.

The present invention is based on the important and surprising discovery that a complement inhibitory protein administered to a subject can modulate complement-related effects of a disorder or disease involving the lung. This discovery led to recognition that pulmonary administration of a complement inhibitory protein, i.e., administration directly to the lung, can result in beneficial effects in the extravascular space, as well as systemic effects.

The present invention is further based in part on the discovery that complement activation is involved in anaphylaxis, and the anaphylactic symptoms of bronchoconstriction and blood pressure changes (hypotension).

It is yet another discovery of the present invention that a complement inhibitory protein can attenuate or prevent bronchoconstriction.

A particular advantage of the present invention is that inhalation therapy is convenient, because it does not involve controlled devices such as syringes, and is fast and generally agreeable. Another advantage of the present invention is that the complement inhibitory protein can e self administered. This is important, since often a subject in need of complement inhibitory therapy is not near to trained medical personnel who could administer the complement inhibitory protein parenterally. Such situations occur, for example, in anaphylaxis due to antigen, and more particularly, allergen exposure; in industries with a likelihood of exposure to dusts and minerals such as silicon, coal dust, beryllium and asbestos; in industries or occupations with a likelihood of exposure to caustic chemicals and gasses such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid; and for firefighters who risk lung tissue damage from inhalation of smoke or hot air.

It is a further advantage of the present invention that the subjects at risk for injury that involves the complement system can use the formulations of the present invention, which comprise a complement inhibitory protein, preferably a CR1 protein, prophylactically. It is demonstrated in an example, infra, that prophylactic administration of a complement inhibitory protein to a subject has no or minimal deleterious effects, and substantially protects the subject from complement-associated injury.

The invention therefore provides for the therapeutic and prophylactic treatment of complement related diseases or disorders, particularly complement related diseases or disorders of the lung, with complement receptor proteins and analogues or derivatives thereof.

In a particular embodiment, the present inventors have discovered that soluble complement receptor type 1 is effective is reducing the bronchoconstriction, hypotension and decrease in circulating platelet count seen in anaphylaxis.

Thus, according to the present invention, formulations are provided which provide an effective noninvasive alternative to other parenteral routes of administration of sCR1. Delivery of complement receptor proteins can be accomplished in the lung via aerosolization and subsequent inhalation.

The invention can be practiced by using any complement receptor protein, or fragment, derivative or analog thereof, including soluble complement receptor. In a preferred embodiment of the present invention, the complement inhibitory protein is Cr1, and more preferably, soluble CR1 (sCR1). Most preferably, the soluble CR1 protein has the characteristics of the protein expressed by a Chinese hamster ovary cell DUX B11 carrying plasmid pBSCR1/pTCSgpt as deposited with the ATCC and assigned accession number CRL 10052.

Claim 1 of 31 Claims

What is claimed is:

1. A method for administering a soluble complement receptor type 1 (sCR1) agent to a subject comprising;

a) providing a sCR1 polypeptide or fragment, derivative, or analog thereof and a pharmaceutically acceptable dispersant in a formulation suitable for pulmonary delivery, wherein said sCR1 polypeptide or fragment, derivative, or analog thereof retains at least one complement-binding activity of an erythrocyte CR1 allotype; and

b) administering said formulation to said subject via the pulmonary route.

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