Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-04-01
2001-04-10
Schwadron, Ronald B. (Department: 1644)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S924000, C424S116000, C530S324000, C530S350000, C530S827000, C530S323000, C530S395000
Reexamination Certificate
active
06214789
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods of treating a subject suffering from infection with Mycobactacteria by administration of Bactericidal/Permeability-Increasing Protein (BPI) protein products. Mycobacterium is a non-motile, acid-fast, aerobic, genus of bacteria known to cause grave human and animal diseases, such as tuberculosis and leprosy. Infections caused by
M. avium
are the most common form of disseminated bacterial disease in AIDS patients. Orme, et al.,
Infect. and Immun.,
61(1):338-342 (1993).
The administration of conventional antibiotics to treat Mycobacterial infection is known in the art and has achieved varying success depending on the susceptibility of the bacterial strain, the efficacy and toxicity of the antibiotic(s) employed, the duration of treatment, and numerous other factors. Antimicrobials that have been employed alone or in combination to treat Mycobacterial infections, including those caused by
M. tuberculosis
include isoniazid, rifampin, ethambutol, p-aminosalicylic acid, pyrazinamide, streptomycin, capreomycin, cycloserine, ethionamide, kanamycin, amikacin, amithiozone, rifabutin, clofazimine, arithromycin, clarithromycin, ciprofloxacin and ofloxacin. McClatchy,
Antimycobacterial Drugs: Mechanisms of Action, Drug Resistance, Susceptibility Testing, and Assays of Activity in Biological Fluids
, pp. 134-197, In
Antibiotics in Laboratory Medicine,
3rd ed., V. Lorian, ed. The Williams & Wilkins Co., Baltimore (1991). As many Mycobacterial strains are drug resistant, serious obstacles exist for control and successful treatment of tuberculosis and other Mycobacterial diseases. Id.
A variety of factors have made treatment of individuals afflicted with Mycobacterial diseases problematic. First, Mycobacteria possess a very hydrophobic cell wall that affords protection against the host's immune system. As Mycobacterial infections tend to be chronic, the pathologies of these organisms are generally due to host response. Also, many Mycobacterial strains are drug-resistant. These and other factors make the development of novel, effective methods for treating Mycobacterial diseases highly desirable.
Mycobacteria are readily distinguished from gram-negative and gram-positive bacteria by acid fast staining due to significant differences in cell wall structure. Gram-negative bacteria are characterized by a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide (LPS), whereas gram-positive bacteria have a cell wall with a thicker layer of peptidoglycan with attached teichoic acids, but no LPS. The Mycobacterial cell wall is rich in fatty acids, including a major constituent, lipoarabinomannan (LAM), which is widely distributed within the cell wall of Mycobacterium species. LAM has been purified from both
M. leprae
and
M. tuberculosis
. Hunter et al,
J Biol. Chem.,
261:12345-12351 (1986). LAM is a serologically active mannose containing phosphorylated lipopolysaccharide that may be membrane associated.
The complex physiological effects of LAM appear to be concentration, time, and source-dependent. For example, Chaterjee et al.,
Infect. and Immun.,
60(3):1249-1253 (1992), reported that, in the first 24 hours following exposure, LAM from an avirulent strain of tuberculosis was 100-fold more potent at stimulating TNF secretion in mouse macrophages than LAM from a virulent strain. LAM concentrations of 0.01-10 &mgr;g/ml for the avirulent strain and 0.01-100 &mgr;g/ml for the virulent strain were tested, and increased LAM concentration was associated with increased TNF production with LAM from both species.
Macrophage-inhibitory effects of LAM have also been described in the art. LAM purified from both
M. leprae
and
M. tuberculosis
has been reported to be a potent in vitro inhibitor of T-cell lymphokine activation of mouse macrophages. Sibley et al.,
Infection and Immunity,
56(5):1232-1236 (1988). Because the principle efferent role of the macrophage in acquired resistance to intracellular pathogens requires activation by T-cell lymphokines, notably gamma-interferon (IFN-&ggr;), macrophages whose activation-response is inhibited are severely compromised in their capacity for both enhanced microbicidal and tumoricidal activities.
In another study, Sibley et al.,
Clin. Exp. Immunol.,
80(1):141-148 (1990), reported that pretreatment of mouse macrophages with 50 to 100 ug/ml LAM blocked macrophage activation by IFN-&ggr;, but pretreatment with 10 &mgr;g/ml LAM did not affect macrophage activation. Thus, it is believed that low concentrations of LAM stimulate cytokine production, at least initially. However, higher concentrations of LAM (50-100 &mgr;g/ml or more) appear to block rather than promote macrophage function. Thus, the production of either too much or too little cytokine at different stages of Mycobacterial disease may contribute to Mycobacterial pathogenesis. New methods for blocking the above-characterized physiological effects of LAM molecules are a highly desirable goal in the treatment of subjects that are or that have been infected with Mycobacteria. For the same reasons, new methods by which fluids containing LAM can be decontaminated prior to administration into a subject are also desirable. Neutralization of even small amounts of LAM is desirable, because small amounts of LAM may have the physiological effect of stimulating cytokine production.
Of interest to the background of the invention are the disclosures of PCT/US88/00510, (WO 88/06038) published Aug. 25, 1988, indicating that certain poloxypropylene/polyoxyethylene nonionic surface-active block copolymers can be used with or without conventional antibiotics to treat infection with Mycobacterium. This reference cites studies suggesting that the effects of other nonionic surfactants on tuberculosis are most likely due to modification of surface lipids of Mycobacteria, and not to direct bactericidal effects on Mycobacteria. See e.g. Cornforth et al.,
Nature,
168:150-153 (1951).
Bactericidal/permeability-increasing protein (BPI) is a protein isolated from the granules of mammalian polymorphonuclear neutrophils (PMN), which are blood cells essential in the defense against invading microorganisms. Human BPI protein has been isolated from PMN's 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), and has 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, as well as the DNA encoding the protein, have been elucidated in
FIG. 1
of Gray, et al.,
J. Biol Chem.,
264: 9505 (1989), incorporated herein by reference.
BPI has been shown to be a potent bactericidal agent active against a broad range of gram-negative bacterial species. The cytotoxic effect of BPI was originally established to be highly specific to sensitive gram-negative species, with no toxicity being noted for other non-acid fast, gram-positive bacteria or for eukaryotic cells. The precise mechanism by which BPI kills bacteria is as yet unknown, but it is known that BPI must first attach to the surface of susceptible gram-negative bacteria. It is thought that this initial binding of BPI to the bacteria involves electrostatic interactions between the basic BPI protein and negatively charged sites on lipopolysaccharides (LPS). LPS has been referred to as endotoxin because of the potent inflammatory response that it stimulates. LPS induces the release of mediators by host inflammatory cells which may ultimately result in irreversible endotoxic shock. BPI binds to Lipid A, the most toxic and most biologically active component of LPS.
In susceptible bacteria, it is thought that BPI binding disrupts LPS structure, leads to an activation of bacterial enzymes that degrade phospholipids and peptidoglycans, alters the permeability of t
Marshall O'Toole Gerstein Murray & Borun
Schwadron Ronald B.
Xoma Corporation
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