Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1998-10-19
2002-12-24
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S145100, C424S158100, C514S885000
Reexamination Certificate
active
06497878
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a preventive or therapeutic agent for cerebral stroke comprising an interleukin-8 (IL-8)-binding-inhibition agent as an active ingredient. The present invention also relates to a preventive or therapeutic agent for cerebral edema comprising an IL-8-binding-inhibition agent as an active ingredient. The present invention also relates to a preventive or therapeutic agent for reperfusion injury of cerebral ischemia comprising an IL-8-binding-inhibition agent as an active ingredient. Furthermore, the present. invention relates to a preventive or therapeutic agent for increased cerebral vascular permeability comprising an IL-8-binding-inhibition agent as an active ingredient.
BACKGROUND ART
IL-8 is a protein that belongs to the C-X-C chemokine subfamily and was formerly designated as the monocyte-derived neutrophil chemotactic factor, the neutrophil attractant/activation protein-1, the neutrophil activating factor and the like. IL-8 is a factor that activates neutrophils and provide them with a migratory ability, and is produced by inflammatory cytokines such as IL-1&bgr; and TNF-&agr; (Koch, A. E. et al., J. Investig. Med. (1995) 43, 28-38; Larsen, C. G. et al., Immunology (1989) 68, 31-36), mitogens such as PMA and LPS (Yoshimura, T. et al, Proc. Natl. Acad. Sci. U.S.A. (1987) 84, 9233-9237), and heavy metals such as Cadmium (Horiguchi, H. et al., Lymphokine Cytokine Res. (1993) 12, 421-428) in a variety of cells. It is also known that human umbilical endothelial cells under a low oxygen condition express IL-8 (Karakurum, M. et al., J. Clin. Invest. (1994) 93, 1564-1570).
In order for IL-8 to exhibit its biological activity, it is necessary that IL-8 binds to IL-8 receptor and thereby stimulates the cells that are expressing IL-8 receptors. IL-8 receptors that transmit signals into the cell by binding to IL-8 have already been cloned and the amino acid sequences thereof have been elucidated. Human IL-8 receptors include those referred to as IL-8 receptor A (&agr; or 2) and those referred to as IL-8 receptor B (&bgr; or 1) (Murphy, P. M. and Tiffany, H. L., Science (1991) 253, 1280-1283; Holmes, W. E. et al., Science (1991) 253, 1278-1280). Both receptors are thought to have a structure that penetrates the cell membrane seven times, and both are associated with GTP-binding proteins in the cytoplasmic domain (Horuk, R., Trends Pharmacol. Sci. (1994) 15, 159-165), and transmit IL-8 signals into the cell. Therefore, inhibition of binding,between IL-8 and IL-8 receptor enables the inhibition of biological activity of IL-8.
The IL-8 binding-inhibition agents so far known include the following substances. As anti-IL-8 antibodies, there are known WS-4 antibody (Ko, Y. et al., J. Immunol. Methods (1992) 149, 227-235), 14E4, 46E5 (Sticherling, M. et al., J. Immunol. (1989) 143, 1628-1634), and human antibody (International Patent Application WO 96/33735), and besides, a polysaccharide (International Patent Application WO 94/18989), a chemical synthetic compound (Sola, F. et al., Invasion Metastasis (1995) 15, 222-231), a peptide fragment (Hayashi, S. et al., J. Immunol. (1995) 154, 814-824), and the like.
With respect to the involvement of IL-8 in reperfusion injury of ischemia, the following findings have been obtained. It has already been reported that in the experimental animal model of reperfusion injury of pulmonary ischemia, the administration of anti-IL-8 antibody at reperfusion following 2 hours of pulmonary ischemia inhibited damages to lung tissues (Sekido, N. et al., Nature (1993) 365, 654-657). On the other hand, though the expression of IL-8 in myocardial tissues after reperfusion has been reported (Ivey, C. L. et al., J. Clin. Invest. (1995) 95, 2720-2728; Kukielka, G. L. et al. J. Clin. Invest. (1995) 95, 89-103), the effect of neutralizing IL-8 is unknown. Rather, it is reported that by administering before reperfusion IL-8 per se that is elevated by reperfusion, the formation of the focus of myocardial infarction is inhibited (Lefer, A. M. et al., Br. J. Pharmacol. (1991) 103, 1153-1159). However, it is unknown whether IL-8 is involved in cerebral infarction, cerebral edema, reperfusion injury of cerebral ischemia, and increased cerebral vascular permeability.
From its mechanism of onset, cerebral apoplexy is classified into the occlusive cerebral vascular injury and the hemorrhagic cerebral vascular injury. The occlusive cerebral vascular injury includes cerebral infarction, and the hemorrhagic cerebral vascular injury includes subarachnoid hemorrhage and cerebral hemorrhage. Cerebral infarction is a condition in which occlusion or decreased perfusion pressure in cerebral and carotid arteries occurred for any reason, thereby causing ischemic necrosis in the brain tissue, and the disease is further divided broadly into the thrombotic, embolic and the hemodynamic infarctions.
The condition in which a sclerotic lesion in the brain arteries combined with increased blood viscosity or decreased perfusion pressure caused anterior occlusion leading to ischemic necrosis is referred to as cerebral thrombosis, the condition in which embolism was formed in the brain artery by intracardiac thrombus or the occasionally ablated mural thrombus of artery is referred to as cerebral embolism, and when the stenosis or occlusion of the cranial and intracranial arteries causes decreased blood flow into the peripheral brain tissues leading to infarction, it is referred to as hemodynamic infarction (Toshio Matobe and Teruo Omae, ed., “Noukekkan Shougai (Cerebral Vascular Injuries),” Life Science Shuppan, 54-55, 1992; Hiroo Imura ed., “Noukekkan Shougai (Cerebral Vascular Injuries),” in Saishin Naikagaku Taikei (Institution of the Latest Internal Medicine), vol. 66, Nakayama Shoten, 28, 1996).
In the brain tissue that has fallen into ischemia because of cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage, the formation of ischemic cerebral edema may be observed. In the case of cerebral infarction, cerebral edema appears a few hours after the onset and persists up to one week after the onset. Thereafter cerebral edema gradually decreases and, depending on the scope of the infarct, becomes fixed as the lesion of the infarct during the one to three months after the onset of the disease. In cerebral hemorrhage, cerebral edema becomes manifest in the periphery of hematoma generally about 6 hours after the onset of the disease due to impaired blood flow at the peripheral territory of the disrupted arteries and impaired circulation and tissue necrosis arising from compression by hematoma (Hiroo Imura ed., “Noukekkan Shougai (Cerebral Vascular Injuries),” in Saishin Naikagaku Taikei (Institution of the Latest Internal Medicine), vol. 66, Nakayama Shoten, 289, 1996).
In the case of subarachnoid hemorrhage, delayed spasm is observed 3 days to 3 weeks after hemorrhage, and the spasm is associated with decreased cerebral perfusion pressure which causes delayed cerebral ischemia. Those unresponsive to treatment develop into cerebral infarction, which in severe cases cause ischemic cerebral edema (Hiroo Imura ed., “Noukekkan Shougai (Cerebral Vascular Injuries),” in Saishin Naikagaku Taikei (Institution of the Latest Internal Medicine), vol. 66, Nakayama Shoten, 163, 1996). Cerebral edema causes an increase in the volume of the brain. Since the brain is covered with the hard cranium, cerebral edema, when it surpasses a certain degree, may cause a sudden rise in tissue pressure and intracranial pressure, which eventually aggravates brain disorders and determines the future scope of the lesion of the infarct (Kenji Inamura and Akiro Kaku, Nippon Rinsho Vol. 51, “CT, MRI Jidaino Nosocchu Gaku, Jokan (Stroke in the Age of CT and MRI, the first volume),” Nippon Rinsho (Japan Clinic), 231-239, 1993). When a part of the brain falls into infarction, the functions carried by the region such as recognition, consciousness, sensation, and memory are lost.
Cerebral edema often occurs in head injuries especially brain contusion, acute subdural hematoma, and a
Ikeda Kiyonobu
Matsumoto Tetsuya
Matsushima Kouji
Yamashita Junkoh
Chan Christina
Chugai Seiyaku Kabushiki Kaisha
DiBrino Marianne
Morrison & Foerster / LLP
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