Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
1999-08-02
2001-11-13
Gambel, Phillip (Department: 1644)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S387100, C530S388100, C435S326000, C435S332000, C435S334000, C435S346000
Reexamination Certificate
active
06316601
ABSTRACT:
BACKGROUND OF THE INVENTION
Integrins are heterodimeric cell adhesion receptors composed of two subunits, &agr; and &bgr;. The integrin &agr;v&bgr;6 is a fibronectin and tenascin receptor expressed predominantly by epithelial cells. In healthy adult primate tissues, &bgr;6 mRNA and protein are rarely detected, although &bgr;6 is expressed during fetal development, wound healing, and in some epithelial tumors. When the &bgr;6 subunit is expressed in a colon carcinoma cell line, from which it is normally absent, expression of the subunit confers an enhanced ability to proliferate. An 11 amino acid COOH-terninal region, unique to the &bgr;6 subunit, is required for the proliferation-enhancing activity of the &agr;v&bgr;6 integrin (Agrez et al.
J. Cell. Biol
. 127:547-556 (1994). &bgr;6 expression is induced in type II aveolar epithelial cells during injury caused by injection of live bacteria, and &bgr;6 expression is observed at focal sites of subclinical inflammation, as well as in a variety of clinical specimens from patients with chronic or acute inflammation of the lungs or kidneys (Breuss et al.
J. Cell Sci
. 108:2241-2251 (1995).
Huang et al. (
J. Cell Biol
. 133:921-928 (1996)) disclosed mice homozygous for a null mutation in the gene encoding the &bgr;6 subunit had juvenile baldness associated with infiltration of macrophages into the skin, and accumulated activated lymphocytes around conducting airways in the lungs.
Pulmonary fibrosis is a common disorder thought to be due to the destructive effects of products released from leukocytes (see, for example, Marshall et al.,
Int. J. Biochem. Cell Bio
. 29:107-120 (1997)). Bleomycin-induced lung injury and pulmonary fibrosis are associated with and may depend upon the recruitment and activation of lymphocytes (Schrier, D. J. et al.,
Am. J. Pathol
. 116:270-278 (1984)). Among proposed therapies for parenchymal lung injury and pulmonary fibrosis is the use of “anticytokine” therapeutic approaches (Coker et al.
Thorax
52 (2): 294-296 (1997)).
However, current therapies for acute lung injury and pulmonary fibrosis are largely inadequate (see, for example, King et al., “Idiopathyic Pulmonary Fibrosis and other Interstitial Lung Diseases of Unknown Etiology,” in
Textbook of Respiratory Medicine
, Murray and Nadel, eds., W. B. Saunders, Philadelphia, Pa., pp. 1827-1839 (1994)). Thus, a need exists for therapies for acute lung injury and pulmonary fibrosis. This need and others are addressed by the instant invention.
SUMMARY OF THE INVENTION
One aspect of the invention is a method of treating acute lung injury in a patient comprising administering to the patient a therapeutic dose of an antagonist of &agr;v&bgr;6. The invention also provides methods of inhibiting lung metastasis comprising administering to the patient a therapeutic dose of an antagonist of &agr;v&bgr;6. A further aspect of the invention is a method of treating fibrosis in a patient comprising administering to the patient a therapeutic dose of an antagonist of &agr;v&bgr;6.
A further aspect of the invention is a monoclonal antibody produced by the hybridoma ATCC HB12382.
A further aspect of the invention is the hybridoma ATCC HB12382.
REFERENCES:
patent: 5514788 (1996-05-01), Bennett et al.
patent: 5654270 (1997-08-01), Ruoslahti et al.
“The Merck Manual of Diagnosis and Therapy”;Merck Professional Handbooks,Sixteenth Edition (1992) pp. 642-646.
Breuss, J. M. et al., “Expression of the &bgr;6 Integrin Subunit in Development, Neoplasia and Tissue Repair Suggests a Role in Epithelial Remodeling”;Journal of Cell Science,108:2241-2251 (1995).
Edgington, S. M. “How Sweet It Is: Selectin-Mediating Drugs”;Biotechnology,10:383-389 (1992).
Kogan, T. P. et al., “A Single Amino Acid Residue Can Determine the Ligand Specificity of E-Selectin”;The Journal of Biological Chemistry,vol. 270, No. 23, Issue of Jun. 9, pp 14047-14055 (1995).
Lehmann, M. et al., “A Monoclonal Antibody Inhibits Adhesion to Fibronectin and Vitronectin of a Colon Carcinoma Cell Line and Recognizes the Integrins”;Cancer Research,54:2102-2107 (Apr. 15, 1994).
Ngo, J. T. et al., “Computational Complexity, Protein Structure Prediction, and the Levinthal Paradox”;The Protein Folding Problem and Tertiary Structure PredictionK. Merz, Jr. and S. Le Grand, Editors © Birkhauser Boston pp. 491-495 (1994).
Rozdzinski, E. et al., “Antiinflammatory Effects in Experimental Meningitis of Prokaryotic Peptides that Mimic Selectins”The Journal of Infectious Diseases,168:1422-8 (1993).
Wang, A. et al., “Differential Regulation of Airway Epithelial Integrins by Growth Factors”;Am. J. Respir. Cell Mol. Biol.,vol. 15:664-672 (1996).
Ward, P. A. et al., “Blocking of Adhesion Molecules In Vivo as Anti-Inflammatory Therapy”Therapeutic Immunology,1:165-171 (1994).
Huang Xiaozhu
Sheppard Dean
Gambel Phillip
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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