Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-02-22
2002-11-19
Kunz, Gary L. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200
Reexamination Certificate
active
06482796
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to novel improved methods of treating subjects that have BPI-reactive anti-neutrophil cytoplasmic antibodies by administering N-terminal bactericidal/permeability-increasing protein (BPI) protein products.
Anti-neutrophil cytoplasmic antibodies (ANCA) have been recognized as a class of autoantibodies that react with the cytoplasmic constituents of neutrophils and monocytes. ANCA are detected by indirect immunofluorescence (IIF) on ethanol-fixed neutrophils, and produce at least three distinct immunofluorescence patterns: cANCA (cytoplasmic, or ‘classic’ pattern), pANCA (perinuclear to nuclear pattern) or aANCA (atypical, with a peculiar “snow drift pattern”). [Kallenberg et al.,
Am. J. Med.,
93:675-682 (1992).] The presence of ANCA has been associated with various idiopathic systemic vasculitis disorders (i.e., inflammation of and damage to the blood vessels) and with other inflammatory disorders, and can be diagnostic of certain vasculitides. These vasculitides are sometimes called ANCA-associated vasculitides (AAV). A pathophysiologic role for ANCA in vasculitides has been proposed but remains to be definitively established. [Kallenberg et al.,
Clin. Exp. Immunol.,
100:1-3 (1995).]
The antigen primarily recognized by c-ANCA proved to be a 29kd serine protease from myeloid azurophilic granules known as proteinase 3 (PR-3). The presence of anti-PR3 is highly correlated to cANCA and is specific for idiopathic vasculitides such as Wegener's granulomatosis (WG), microscopic polyarteritis (MPA) and the renal limited pauci-immune necrotizing and crescentic glomerulonephritis (NCGN). [Kallenberg, 1995, supra.]
One of the antigens recognized by p-ANCA is myeloperoxidase (MPO), another constituent of azurophilic granules. However, only a minority of p-ANCA-positive sera reacts with MPO. Anti-MPO antibodies have been found to be specific for systemic vasculitis and idiopathic crescentic glomerulonephritis. Anti-MPO antibodies are also found in patients with anti-glomerular basement membrane disease and in some sera of patients with systemic lupus erythematosus (SLE). The presence of p-ANCA has also been described in sera from patients with a wide range of different disorders such as colitides (including ulcerative colitis, inflammatory bowel disease, Crohn's disease and collagenous colitis), autoimmune liver diseases (including autoimmune chronic active hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis) and rheumatoid arthritis. [Kallenberg, 1992, supra.] These latter p-ANCA generally do not react with MPO, and their antigenic specificities are largely unknown. Some antibodies to leukocyte elastase and lactoferrin have also been described that produce a p-ANCA pattern by IIF. Antibodies to elastase occur occasionally in sera from patients with vasculitis or drug-induced systemic autoimmune disease. Lactoferrin antibodies have been seen in a few patients with vasculitis, primary sclerosing cholangitis and ulcerative colitis, and in a minority of patients with rheumatoid arthritis. Their diagnostic value has not been established yet.
BPI has been identified as another ANCA antigen. Falk et al., Third Int'l Workshop on ANCA,
Am J. Kidney Dis.,
18:197 (abst. 6) (1991), reported that 11 of 51 cANCA-positive samples recognized a 57-kD antimicrobial cationic protein (CAP57), which was later identified as BPI by N-terminal amino acid sequence homology and immunoreactivity. This CAP57-specific cANCA staining was blocked by anti-CAP57 monoclonal antibodies but not by anti-MPO or anti-PR3 monoclonal antibodies. No clinical details of the patients, with respect to whether or not they had vasculitis, and if so, the distribution, were reported in this abstract.
Zhao et al.,
Clin. Exp. Immunol.,
99:49-56 (1995) also reported the identification of BPI-reactive ANCA in serum samples from patients with suspected vasculitis. Of 100 historical serum samples that were double-negative for PR3 and MPO specificity by ELISA, 45% were reactive with purified BPI. Of 400 newly obtained samples sent for routine ANCA testing, 11% had BPI specificity, suggesting that BPI is an important ANCA antigen. The PR3 and MPO specificities in these 400 new samples were 10/400 and 14/400 respectively. Zhao et al. conjectured that these human autoantibodies against BPI might block the bactericidal and LPS-neutralizing activities of BPI, allowing these non-neutralized products to directly cause vascular damage and initiate vasculitis.
BPI is a protein isolated from the granules of mammalian polymorphonuclear leukocytes (PMNs or neutrophils), which are blood cells essential in the defense against invading microorganisms. Human BPI protein has been isolated from PMNs by acid extraction combined with either ion exchange chromatography [Elsbach,
J. Biol. Chem.,
254:11000 (1979)] or
E. coli
affinity chromatography [Weiss, et al.,
Blood,
69:652 (1987)]. BPI obtained in such a manner is referred to herein as natural BPI and has been shown to have potent bactericidal activity against a broad spectrum of gram-negative bacteria. The molecular weight of human BPI is approximately 55,000 daltons (55 kD). The amino acid sequence of the entire human BPI protein and the nucleic acid sequence of DNA encoding the protein have been reported in FIG. 1 of Gray et al.,
J. Biol. Chem.,
264:9505 (1989), incorporated herein by reference. The Gray et al. amino acid sequence is set out in SEQ ID NO: 1 hereto. U.S. Pat. No. 5,198,541 discloses recombinant genes encoding and methods for expression of BPI proteins, including BPI holoprotein and fragments of BPI.
BPI is a strongly cationic protein. The N-terminal half of BPI accounts for the high net positive charge; the C-terminal half of the molecule has a net charge of −3. [Elsbach and Weiss (1981), supra.] A proteolytic N-terminal fragment of BPI having a molecular weight of about 25 kD possesses essentially all the anti-bacterial efficacy of the naturally-derived 55 kD human BPI holoprotein. [Ooi et al.,
J. Bio. Chem.,
262: 14891-14894 (1987)]. In contrast to the N-terminal portion, the C-terminal region of the isolated human BPI protein displays only slightly detectable anti-bacterial activity against gram-negative organisms. [Ooi et al.,
J. Exp. Med.,
174:649 (1991).] An N-terminal BPI fragment of approximately 23 kD, referred to as “rBPI
23
,” has been produced by recombinant means and also retains anti-bacterial activity against gram-negative organisms. [Gazzano-Santoro et al.,
Infect. Immun.
60:4754-4761 (1992).] An N-terminal analog of BPI, rBPI
21
, has been produced as described in Horwitz et al.,
Protein Expression Purification,
8:28-40 (1996).
The bactericidal effect of BPI has been reported to be highly specific to gram-negative species, e.g., in Elsbach and Weiss,
Inflammation: Basic Principles and Clinical Correlates,
eds. Gallin et al., Chapter 30, Raven Press, Ltd. (1992). The precise mechanism by which BPI kills gram-negative bacteria is not yet completely elucidated, but it is believed that BPI must first bind to the surface of the bacteria through electrostatic and hydrophobic interactions between the cationic BPI protein and negatively charged sites on LPS. In susceptible gram-negative bacteria, BPI binding is thought to disrupt LPS structure, leading to activation of bacterial enzymes that degrade phospholipids and peptidoglycans, altering the permeability of the cell's outer membrane, and initiating events that ultimately lead to cell death. [Elsbach and Weiss (1992), supra]. LPS has been referred to as “endotoxin” because of the potent inflammatory response that it stimulates, i.e., the release of mediators by host inflammatory cells which may ultimately result in irreversible endotoxic shock. BPI binds to lipid A, reported to be the most toxic and most biologically active component of LPS.
BPI protein products, as discussed infra, h
Gucker Stephen
Kunz Gary L.
Marshall Gerstein & Borun
Xoma Corporation
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