Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2000-05-17
2004-03-30
Navarro, Mark (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S190100, C424S234100, C435S975000, C530S300000, C530S324000, C530S326000, C530S327000, C530S328000, C530S350000
Reexamination Certificate
active
06713062
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of genes and proteins derived from pathogenic bacteria. More particularly, the invention provides Acinetobacter outer membrane protein and gene compositions and methods for making and using a range of biological components related thereto. The invention thus provides nucleic acids, proteins, peptides and antibodies for use in various diagnostic and therapeutic applications, including those connected with peptic ulcers and cancers, respiratory diseases, sepsis and other conditions.
2. Description of Related Art
Helicobacter pylori
(
H. pylori
) causes chronic gastritis and is correlated with the development of peptic ulcer disease and gastric carcinoma (Marshall et al, 1994; Graham, 1998; Nomura et al., 1991). However, there is also a potential association between colonization of the stomach by non-Helicobacter organisms and gastric atrophy and gastritis (Elliott et al., 1998; Haruma et al., 1995; Saunders et al., 1998).
Studies in the human and monkey have clearly shown that bacteria are important in triggering mucosal damage and inflammation in the stomach (Khanolkar-Gaitonde et al., 2000; Stockbruegger et al., 1984). It is not currently known whether colonization by non-Helicobacter organisms triggers perturbations in the neuroendocrine and epithelial cell populations. The implications being that the pathology observed may not be specific for
H. pylori
, but instead is the general response of the gastric mucosa to bacteria.
H. pylori
is characterized by its ability to survive in the low-pH environment of the stomach by generating an alkaline microenvironment. However, with reduced levels of acid (hypochlorhydria or achlorhydria), the competitive niche established by
H. pylori
dissipates and the human stomach is colonized by other organisms (Haruma et al., 1995; Lehy et al., 2000). The colonization with aerobic and anaerobic flora that occurs in the stomach with increasing pH (Torres et al., 1996) may be the result of increasing age, malnutrition or iatrogenically induced achlorhydria, e.g., H2-receptor blockade or proton-pump inhibitor administration. Importantly, chronic achlorhydria is a risk factor for gastric cancer (Seery, 1991). With the exception of “stress ulcer” treatment, the bacterial flora present under conditions of hypochlorhydria has been poorly studied.
Patients in intensive care units often have a gastric pH of >3 due to the routine use of antacids, proton pump inhibitors or H2-receptor antagonists to prevent “stress ulcers”. An increase in gastric pH permits colonization of the stomach with opportunistic pathogens that contribute to the development of nosocomial pneumonia (Garrouste-Orgeas et al., 1997). Bacteria cultured from the relatively alkaline stomachs of ventilated patients (Garrouste-Orgeas et al, 1997) have been implicated in nosocomial respiratory infections (Craven et al., 1990). In a study examining oropharyngeal and gastric colonization using DNA genomic analysis, gastric colonization occurred regardless of the pH, which ranged from 2.8 to 5.7. Antacids were not used and H2-receptor antagonists were used occasionally. A notable incidence if nosocomial pneumonias was reported in ventilated patients, despite the use of broad-spectrum antibiotics, e.g., amoxicillin and aminoglycosides.
As pathogenic organisms evidently exist that are able to evade or counteract currently available antibiotics, there is a need in the art to identify organisms and virulence factors from gastric bacterial flora that cause or contribute to gastric and systemic diseases. The identification of a surface accessible molecule from such a pathogenic organism would be a significant advance, leading long sought after diagnostics and therapeutics.
SUMMARY OF THE INVENTION
The present invention overcomes these and other drawbacks inherent in the prior art by linking Acinetobacter with various diseases and disorders and by providing Acinetobacter outer membrane protein A (OMP A) protein and gene compositions for therapeutics and diagnostics. The OMP A nucleic acid, protein, peptide and antibody compositions thus provided are useful in a variety of embodiments, including the diagnosis and therapy of peptic ulcers and cancers, respiratory diseases, sepsis and other conditions. Uses of the invention as part of a battery of diagnostic agents and in combination therapies are also provided.
The invention thus provides isolated nucleic acid molecules or segments comprising at least a first isolated coding region of at least about 800, 850, 900, 910, 920, 930, 940, 950, 960, 970 or 980 nucleotides or so in length that specifically hybridizes, preferably under conditions of stringency, and more preferably under conditions of high stringency, to the coding region of the nucleotide sequence set forth in SEQ ID NO:1 or to the coding region of the nucleotide sequence set forth in SEQ ID NO:6.
The at least a first isolated coding regions are those wherein:
(a) the coding sequence is a coding sequence of a DNA molecule present in a bacterial gene library, wherein the DNA molecule hybridizes with a probe having the sequence of the complement of SEQ ID NO:1 under conditions of high stringency; or
(b) the coding sequence has a nucleotide sequence degenerate with a sequence according to (a), above.
The invention also provides isolated nucleic acid molecules or segments comprising at least a first isolated coding region that encodes a protein or polypeptide comprising an amino acid sequence that is at least about 85%, 86%, 87%, 88%, 89%, 90%, 91% 92% 93% 94% 95% 96% 97% 98% or 99% or so identical to amino acids 22-349 of the amino acid sequence of SEQ ID NO:2. The encoded proteins and polypeptides are Acinetobacter outer membrane proteins and polypeptides or are able to generate antibodies that cross-react therewith.
Co-owned U.S. Pat. No. 6,074,840 is specifically incorporated herein by reference for purposes of supplementing the present description and enabling teaching concerning isolated nucleic acid molecules that comprise sequences encoding contiguous amino acids sequences; that encode proteins or polypeptides that exhibit at least 90% identity to a given amino acid sequence, wherein the proteins or polypeptides maintain the function of the protein or polypeptide of the given amino acid sequence; and that encode nucleic acid molecules that comprise the nucleotide sequence of a coding sequence of a DNA molecule present in a gene library, wherein the DNA molecule hybridizes with a probe having a given sequence under conditions of high stringency or nucleotide sequences degenerate with such hybridizing sequences.
Exemplary nucleic acid segments of the invention comprise at least a first isolated coding region of at least about 980 nucleotides in length that specifically hybridizes to the nucleotide sequence between nucleotide 1 and about 1050 of SEQ ID NO:1 or an isolated coding region that encodes a protein that comprises at least amino acids 22-349 of the amino acid sequence of SEQ ID NO:2.
Further nucleic acid segments comprise at least a first isolated coding region of at least about 980 nucleotides in length that specifically hybridizes to the nucleotide sequence between nucleotide 63 and about 1050 of SEQ ID NO:1 or an isolated coding region that encodes a protein that comprises at least amino acids 22-349 of the amino acid sequence of SEQ ID NO:2.
Other nucleic acid segments comprise at least a first isolated coding region of at least about 1050 nucleotides in length that specifically hybridizes to the coding region within the nucleotide sequence of SEQ ID NO:1 or to the coding region of the nucleotide sequence set forth in SEQ ID NO:6 or an isolated coding region that encodes a protein comprising an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO:2.
Still further nucleic acid segments comprise at least a first isolated coding region of at least about 1050 nucleotides in length that specifically hybridizes to the nucleotide s
Navarro Mark
The Regents of The University of Michigan
Williams, Morgan and Amerson
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