Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Utility Patent
1998-06-19
2001-01-02
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S009200, C530S388400, C530S388250
Utility Patent
active
06168790
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods and compositions for preventing or treating disease states caused by bacteria. More particularly, the present invention relates to antibodies and molecules that mediate cellular activation in response to Gram-positive bacteria and mycobacteria.
2. Description of Related Art
Septic shock is a tragic complication of bacterial infections, characterized by refractory hypotension, leading to inadequate organ perfusion, multiple organ failure and frequently death (Glauser, et al.,
Lancet,
338:732-736, 1991; Bone,
Chest,
100:802-808, 1991). The lipopolysaccharide (endotoxin, LPS) of Gram-negative bacteria triggers cellular and physiological responses such as those observed during Gram-negative sepsis (Glauser, et al., supra; Ulevitch and Tobias,
Curr. Opin. Immunol.
6:125-130, 1994). Cells of the immune/inflammatory systems respond to LPS by a pathway involving both plasma and membrane proteins (Ulevitch and Tobias, supra, 1994; Tobias, et al.,
Am. J Respir. Cell Mol. Biol.,
7:239-245, 1992). Included in this group of proteins are lipopolysaccharide-binding protein (LBP), a soluble serum protein which binds LPS and subsequently enables the binding of LPS to a second molecule, CD14. The LBP/CD14-dependent pathway is operative under physiological conditions and controls cell activation when nanomolar concentrations of LPS are used (Schumann, et al.,
Science,
249:1429-1433, 1990; Wright, et al.,
Science,
249:1431-1433, 1990). CD14 is found as a glycosylphosphatidylinositol-anchored membrane protein (mCD14) of myeloid cells, or in plasma/serum as a soluble protein (sCD14) (Ulevitch and Tobias, supra, 1994; Tobias, et al., supra, 1992; Pugin, et al.,
Proc. Natl. Acad. Sci. USA,
90:2744-2748, 1993a). Binding of LPS to mCD14 leads to cellular activation and generation of various proinflammatory molecules (Ulevitch and Tobias, supra, 1994). Other cell types such as endothelial, epithelial, vascular smooth muscle cells, and astrocytes do not bear CD14 but respond to soluble CD14-LPS complexes (Pugin, et al., supra, 1993a; Frey, et al.,
J. Exp. Med.,
176:1665-1671, 1992). A CD14-and LBP-independent pathway of LPS stimulation is observed only when high LPS concentrations are used.
In recent multicenter trials on sepsis, Gram-positive bacteria were found responsible for half of the cases of bacterial sepsis (Bone,
Arch. Intern. Med.,
154:26-34, 1994). The prevalence of sepsis due to Gram-positive bacteria has risen markedly over the past two decades, and those microorganisms may well predominate as the cause of sepsis within the next few years (Bone, supra, 1994; Schaberg, et al.,
Am. J. Med.,
91:72S-75S, 1991). In contrast to what has been learned about how LPS stimulates cells much less is known about the molecular mechanisms of cellular activation by Gram-positive bacteria. Products of Gram-positive bacteria that can activate host cells include soluble exotoxins and cell wall components (Bone, supra, 1994). It is known that cell walls isolated from different Gram-positive strains, as well as purified cell wall components such as peptidoglycan or lipoteichoic acid activate cells of myeloid origin and induce cell responses very similar to that of LPS (Chin and Kostura,
J. Immunol.,
151:5574-5585, 1993; Mattson, et al.,
FEMS Immun. Med. Microbiol.,
7:281-288, 1993; Rotta, Z.
Immunol.—Forsch, Bd.,
149-230-244, 1975). However, few studies have addressed the mechanisms of receptor-dependent recognition of Gram-positive cell wall components by mammalian cells.
The hypothesis of pattern-recognition receptors advanced by Janeway (
Today,
13:11-16, 1992) suggests that common cellular recognition pathways might be involved in responses to molecules with similar structural features from a variety of pathogens. There are currently no data to support this hypothesis except a report that lipoarabinomannan (LAM) from
Mycobacterium tuberculosis
activated a human monocytic cell line by CD14-dependent mechanisms (Zhang, et al.,
J. Clin. Invest.,
91:2076-2083, 1993). In addition, the group of Espevik, et al. (
Eur. J. Immunol.,
23:255-261, 1993; Otterlei, et al.,
Infect. Immun.,
61:1917-1925, 1993) identified S1-4 linked polyuronic acid polymers from different origins, including Pseudomonas species, capable of stimulating human monocytes in a CD14-dependent manner. However, a recent study suggested that release of tumor necrosis factor (TNF) by human peripheral blood monocytes stimulated with large amounts of Gram-positive cell wall components was not inhibited by a monoclonal antibody to human CD14, MY4, that does block LPS-induced TNF release under some experimental conditions (Heumann, et al.,
Infect. Immun.,
69:2715-1721, 1994).
To explore in more detail the role of mCD14 or sCD14 in mediating cellular responses to cell wall preparations from Gram-positive organisms and to mycobacterial LAM, responses of CD14-positive and CD14-negative cell lines to these agonists in the presence and absence of anti-CD14 antibodies were compared. Evidence for a CD14 dependent activation of cells by gram-positive cell wall preparations and by LAM is shown. These data provide new information about pathways of cell activation used by Gram-positive bacteria and mycobacteria and lend support to the concept of pattern recognition receptors in cells of the immune system.
Current concepts support the contention that the primary response of the host to LPS (including man) involves the recognition of LPS by cells of the monocyte/macrophage lineage, followed by the rapid elaboration of a variety of cell products including the general group known as cytokines. Other cell types believed to participate in sepsis and in particular in the response to LPS are polymorphonuclear leukocytes and endothelial cells; each of these cell types are also capable of responding to LPS with the elaboration of potent inflammatory substances.
LPS is believed to be a primary cause of death in humans during gram-negative sepsis, particularly when the symptoms include adult respiratory distress syndrome (ARDS) (van Deventer, et al.,
Lancet,
1:605, 1988; Ziegler, et al.,
J. Infect. Dis.,
136:19-28, 1987). For instance, one particular cytokine, tumor necrosis factor alpha/cachectin (TNF), has recently been reported to be a primary mediator of septic shock (Beutler, et al.,
N. Eng. J. Med.,
316:379, 1987). Intravenous injection of LPS endotoxin from bacteria into experimental animals and man produces a rapid, transient release of TNF (Beutler, et al.,
J. Immunol.,
135:3972, 1985; Mathison, et al.,
J. Clin. Invest.,
81:1925, 1988). Evidence that TNF is a critical mediator of septic shock comes primarily from experiments in which pretreatment of animals with anti-TNF antibodies reduces lethality (Beutler, et al.,
Science,
229:869, 1985; Mathison, et al.,
J. Clin. Invest.,
81:1925, 1988). These reports suggest that interruption of the secretion of TNF caused by LPS or other factors would ameliorate the often lethal symptoms of sepsis.
Upon introduction of LPS into the blood, it may bind to a protein termed lipopolysaccharide binding protein (LBP). LBP is a 60 kD glycoprotein present at concentrations of less than 100 ng/ml in the serum of healthy animals and man. During the acute phase, LBP is synthesized by hepatocytes, and reaches concentrations of 30-50 ug/ml in serum. LBP can be purified from acute phase human and rabbit serum (Tobias, et al.,
J. Exp. Med.,
164:777-793, 1986). LBP recognizes the lipid A region of LPS and forms high affinity, 1:1 stoichiometric complexes with both rough and smooth form LPS (Tobias, et al., 264:10867-10871, 1989). LBP bears N-terminal sequence homology with the LPS-binding protein known as bactericidal permeability-increasing factor, (BPI) (Tobias, et al., supra, 1988). BPI is stored in the specific granules of PMN (Weiss, et al.,
Blood,
69:652-659,1987) and kills gram negative bacteria by binding LPS and disrupting the permeability barrier (Weiss, et al.,
J. Immunol.,
132:3109-311
Pugin Jerome
Tobias Peter S.
Ulevitch Richard J.
Gray Cary Ware & Freidenrich LLP
Haile Lisa A.
Portner Ginny Allen
Smith Lynette R. F.
The Scripps Research Institute
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