Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Utility Patent
1995-08-11
2001-01-02
Fitzgerald, David L. (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S008100, C424S499000
Utility Patent
active
06169068
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to formulations for pulmonary administration by inhalation that comprise a complement inhibitory protein and uses thereof in the prophylactic or therapeutic treatment of disease or disorders involving complement, especially of the lung. In particular, the proteins are complement receptors or fragments thereof or soluble members of the complement receptor family that contain the conserved SCR motif and that are able to inhibit complement activity. More particularly the present invention relates to the direct treatment of certain complement related lung disorders by administering complement receptor proteins via the pulmonary route, in particular, direct delivery to the lungs of a complement receptor protein by aerosolization and subsequent inhalation. The invention also relates to use of a complement inhibitory protein to treat bronchoconstriction or anaphylaxis, or both.
BACKGROUND OF THE INVENTION
The Complement System
The complement system is a group of proteins that constitute about 10 percent of the globulins in the normal serum of humans (Hood, L. E., et al., 1984, Immunology, 2d Ed., The Benjamin/Cummings Publishing Co., Menlo Park, Calif., p. 339). Complement (C) plays an important role in the mediation of immune and allergic reactions (Rapp, J. J. and Borsos, T, 1970, Molecular Basis of Complement Action, Appleton-Century-Crofts (Meredity), New York). The activation of complement components leads to the generation of a group of factors, including chemotactic peptides that mediate the inflammation associated with complement dependent diseases. The sequential activation of the complement cascade may occur via the classical pathway involving antigen-antibody complexes, or by an alternative pathway which involves the recognition of certain cell wall polysaccharides. The activities mediated by activated complement proteins include lysis of target cells, chemotaxis, opsonization, stimulation of vascular and other smooth muscle cells, and functional aberrations such as degranulation of mast cells, increased permeability of small blood vessels, directed migration of leukocytes, and activation of B lymphocytes and macrophages (Eisen, H. N., 1974, Immunology, Harper & Row Publishers, Inc. Hagerstown, Md., p. 512).
During proteolytic cascade steps, biologically active peptide fragments, the anaphylatoxins C3a, C4a, and C5a (See WHO Scientific Group, 1977, WHO Tech, Rep. Ser. 606:5 and references cited therein), are released from the third (C3), fourth (C4), and fifth (C5) native complement components (Hugli, T. E., 1981, CRC Crit. Rev. Immunol. 1:321; Bult, H. and Herman, A. G., 1983, Agents Actions 13:405).
Complement Receptors
COMPLEMENT RECEPTOR 1 (CR1). The human C3b/C4b receptor, termed CR1 or CD35, is present on erythrocytes, monocytes/macrophages, granulocytes, B cells, some T. cells, splenic follicular dendritic cells, and glomerular podocytes (Fearon D. T., 1980, J. Exp. Med. 152:20, Wilson, J. G., et al., 1983, J. Immunol. 131:684; Reynes, M., et al., 1976 N. Engl. J. Med. 295:10; Kazatchkine, M. D., et al., 1982, Clin. Immunol. Immunopathol. 27:210). CR1 specifically binds C3b, C4b and iC3b.
CR1 can inhibit the classical and alternative pathway C3/C5 convertases and act as a cofactor for the cleavage of C3b and C4b by factor I, indicating that CR1 also has complement regulatory functions in addition to serving as a receptor (Fearon, D. T., 1979, Proc. Natl. Acad. Sci. U.S.A. 76:5867; Iida, K. I. and Nussenzweig, V., 1981, J. Exp. Med. 153:1138). In the alternative pathway of complement activation, the bimolecular complex C3b,Bb is a C3 enzyme (convertase). CR1 (and factor H, at higher concentrations) can bind to C3b and can also promote the dissociation of C3b,Bb. Furthermore, formation of C3b,CR1 and (C3b,H) renders C3b susceptible to irreversible proteolytic inactivation by factor I, resulting in the formation of inactivated C3b (iC3b). In the classical pathway of complement activation, the complex C4b,2a is the C3 convertase.
CR1 (and C4 binding protein, C4bp, at higher concentrations) can bind to C4b, and can also promote the dissociation of C4b,2a. The binding renders C4b susceptible to irreversible proteolytic inactivation by factor I through cleavage to C4c and C4d (inactivated complement proteins).
CR1 has been shown to have homology to complement receptor type 2 (CR2) (Weis, J. J., et al., 1986, Proc. Natl. Acad. Sci. U.S.A. 83:5639-4643). CR1 is a glycoprotein comprising multiple short consensus repeats (SCRs) arranged in 4 long homologous repeats (LHRs). The most C-terminal LHR called LHR-D is followed by 2 additional SCRs, a transmembrane region and a cytoplasmic region (Klickstein, et al., 1987, J. Exp. Med., 165:1095; Klickstein, et al., 1988, J. Exp. Med., 168:1699-1717). Erythrocyte CR1 appears to be involved in the removal of circulating immune complexes in autoimmune patients and its levels may correlate with the development of AIDS (Inada, et al., 1986, AIDS Res. 2:235; Inada, et al., 1989, Ann. Rheu. Dis. 4:287).
Four allotypic forms of CR1 have been found, differing by increments of 40,000-50,000 daltons molecular weight. The two most common forms, the F and S allotypes, also termed the A and B allotypes, have molecular weights of 250,000 and 290,000 daltons (Dykman, T. R., et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:1698; Wong, W. W., et al., 1983, J. Clin. Invest. 72:685), respectively, and two rarer forms have molecular weights of 210,000 and 290,000 daltons (Dykman, T. R., et al., 1984, J. Exp. Med. 159:6891; Dykman, T. R., et al., 1985, J. Immunol. 134:1787). These differences apparently represent variations in the polypeptide chain of CR1, rather than glycosylation state, because they were not abolished by treatment of purified receptor protein with endoglycosidase F (Wong, W. W., et al., 1983, J. Clin. Invest. 72:685), and they were observed when receptor allotypes were biosynthesized in the presence of the glycosylation inhibitor tunicamycin (Lublin, D. M., et al., 1986, J. Biol. Chem. 261:5736). All four CR1 allotypes have C3b-binding activity (Dykman, T. R., et al., 1983, Proc. Natl. Acad. Sci. U.S.A. 80:1698; Wong, W. W., et al., 1983, J. Clin. Invest. 72:685; Dykman, T. R., et al., 1984, J. Exp. Med., 159:691; Dykman, T. R., et al., 1985, J. Immunol. 134:1787). There are four LHRs in the F (or A) allotype of ~250 kD, termed LHR-A, -B, -C, and -D, respectively, 5′ to 3′ (Wong, et al., 1989, J. Exp. Med. 169:847). While the first two SCRs in LHR-A determine its ability to bind C4b, the corresponding units in LHR-B and -C determine their higher affinities for C3b. The larger S (or B) allotype of ~290 kd has a fifth LHR that is a chimera of the 5′ half of LHR-B and the 3′ half of LHR-A and is predicted to contain a third C3b binding site (Wong, et al., 1989, J. Exp. Med. 169:847). The smallest F′ (or C) allotype of CR1 of ~210 kD, found in increased incidence in patients with SLE and associated with patients in multiple lupus families (Dykman, et al., 1984, J. Exp. Med. 159:691; Van Dyne, et al., 1987, Clin. Exp. Immunol. 68:570), may have resulted from the deletion of one LHR and may be impaired in its capacity to bind efficiently to immune complexes coated with complement fragments.
A naturally occurring soluble form of CR1 has been identified in the plasma of normal individuals and certain individuals with SLE (Yoon, et al., 1985 J. Immunol. 134:3332-3338). Its structural and functional characteristics are similar to those of erythrocyte (cell surface) CR1, both structurally and functionally. Hourcade, et al. (1988, J. Exp. Med. 168:1255-1270) also observed an alternative polyadenylation site in the human CR1 transcriptional unit that was predicted to produce a secreted form of CR1 containing C4b binding domain.
Several soluble fragments of CR1 have also been generated via recombinant DNA procedures by eliminating the transmembrane region from the DNAs being expressed (Fearon, et al., Intl. Patent Publ. WO 89/09220, Oct. 5, 1989; Fearon, et al., Intl.
Levin James L.
Regal Jean F.
Toth Carol A.
Avant Immunotherpeutics, Inc.
Fitzgerald David L.
Yankwich Leon R.
Zwicker Kenneth P.
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