Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-12-16
1999-01-05
Spector, Lorraine
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 4241921, 530350, C07K 14435, A61K 3817
Patent
active
058563024
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention provides bactericidal/permeability-increasing protein (BPI) dimer products characterized by enhanced in vivo biological activity and stable pharmaceutical compositions containing the same.
Lipopolysaccharide (LPS) is a major component of the outer membrane of gram-negative bacteria and consists of serotype-specific O-side-chain polysaccharides linked to a conserved region of core oligosaccharide and lipid A. Raetz, Ann. Rev. Biochem., 59:129-170 (1990). LPS is an important mediator in the pathogenesis of gram-negative septic shock, one of the major causes of death in intensive-care units in the United States. Morrison, et al., Ann. Rev. Med. 38:417-432 (1987).
LPS-binding proteins have been identified in various mammalian tissues. Morrison, Microb. Pathol., 7:389-398 (1989); Roeder, et al., Infect., Immun., 57: 1054-1058 (1989). Among the most extensively studied of the LPS-binding proteins is bactericidal/permeability-increasing protein (BPI), a basic protein found in the azurophllic granules of polymorphonuclear leukocytes. Human BPI protein has been isolated from polymorphonuclear neutrophils by acid extraction combined with either ion potent bactericidal activity against a broad spectrum of gram-negative bacteria.
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 (SEQ ID NOS: 1 and 2). The Gray et al. publication discloses the isolation of human BPI-encoding cDNA from a cDNA library derived from DMSO-induced cells of the human promyelocytic leukemia HL-60 cell line (ATTC CCL 240). Multiple PCR amplifications of DNA from cDNA library derived from such DMSO-induced HL-60 cells as well as DNA from normal human blood and bone marrow cell have revealed the existence of human BPI-encoding cDNAs wherein the codon specifying valine at amino acid position 151 is either GTC (as set out in SEQ ID No: 1) or GTG. Moreover, cDNA species employing GTG to specify valine at position 151 have also been found to specify either lysine (AAG) for the position 185 amino acid (as in SEQ ID Nos: 1 and 2) or a glutamic acid residue (GAG) at that position.
A proteolytic fragment corresponding to the N-terminal portion of human BPI holoprotein possesses the antibacterial activity of the naturally-derived 55 kDa human BPI holoprotein. In contrast to the N-terminal portion, the C-terminal region of the isolated human BPI protein displays only slightly detectable anti-bacterial activity. Ooi, et al., J. Exp. Med., 174:649 (1991). A BPI N-terminal fragment designated rBPI.sub.23, Gazzano-Santoro et al., Infect. Immun. 60:4754-4761 (1992), and comprising approximately the first 199 amino acids of the human BPI holoprotein, has been produced by recombinant means as a 23 kD protein.
The bactericidal effect of BPI has been shown to be highly specific for sensitive gram-negative species. The precise mechanism by which BPI kills bacteria is not yet completely elucidated, but it is known that BPI must first attach to the surface of susceptible gram-negative bacteria. This initial binding of BPI to the bacteria involves electrostatic and hydrophobic interactions between the basic BPI protein and negatively charged sites on LPS. 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, the most toxic and most biologically active component of LPS.
In susceptible 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, Weiss, Inflammation: Basic Principles and Clinical Correlates, eds. Galin et al., Chapter 30, Raven Press, Ltd. (1992)!. BPI is thought to act in two stages. The first is a sublethal stage th
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Ammons William Steve
Little Roger G.
Spector Lorraine
Xoma Corporation
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