Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1996-10-17
1999-01-05
Scheiner, Toni R.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
4241331, 4241411, 4241431, 4241441, 4241521, 4241541, 5303873, 5303882, 53038822, 53038873, 53038875, 53038885, 5303896, A61K 39395, C07K 1628
Patent
active
058558888
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP95/00527 filed Mar. 22, 1995.
DESCRIPTION
1. Technical Field
This invention relates to a drug for the treatment of rheumatoid arthritis which comprises as an active ingredient a monoclonal antibody which can specifically recognize extracellular region of human VLA-2.
2. Technical Background
Rheumatoid arthritis (hereinafter, abbrebiated as "RA") is a chronic inflammatory disease which shows an inflammatory symptom mainly in the articular synovial membrane, where various inflammatory cells permeate into synovial fluid through hemangioendotheliocytes of synovial membrane. It is assumed that the pathological symptoms may be participated by immunological mechanism, and the symptoms may become a trigger of immuno-response, but it is still difficult to specify the mechanism. It is also important to make clear the reason why the inflammatory symptoms are maintained at the synovial membrane even after the cause of the disease has been removed. A series of processes of these inflammation symptoms, particularly chronicity and duration thereof, will be deeply participated by lymphocytes which take charge of immunization.
Panayi, G. S. et al mentioned as "Synovitis (associated with RA) is no longer conceived as an antibody-mediated process involving rheumatoid factors and immune complexes, but rather as a cell-mediated process involving T cells, antigen-presenting cells (APC), macrophages, synoviocytes, and cytokines." (cf. Arth. Rheum., 35, pp.729-735, 1992).
Kakimoto, K. et al. reported that when an anti-ICAM-1 antibody or anti-LFA-1 antibody was administered to a model of mouse suffered from collagen-induced arthritis (hereinafter abbreviated as "CIA") from the stage of the first sensitization with an antigen which is induction phase pp.326-337 (1992)!. It was further reported by Kakimoto et al. at the 23rd General Assembly of Japan Immunological Association that when a combination of an anti-ICAM-1 antibody and an anti-LFA-1 antibody was administered from the stage of the first sensitization with an antigen, the CIA was more effectively suppressed in rats in comparison with the Association, General Assembly Documents, 23, p.530, 1-28 (1993)!.
Besides, Durie, F. H. et al. reported that in a mouse CIA model, CIA was suppressed by the administration of anti-CD 40 ligand (CD40L) antibody pp.1328-1330 (1993)!.
On the other hand, it has been considered that collagen, fibronectin, laminin and proteoglycan, which are matrix molecules in synovial tissue, participate in fixation and retention of lymphocytes and macrophage into the tissue or activation thereof via VLA family. These participate deeply in the lesion of synovial membrane in RA, and hence, the clearance of the mechanism thereof is important for finding a suitable means of the treatement of RA.
Miyake, S. et al. have investigated the change of mRNA of cytokines where monocytes separated from the synovial fluid of RA patients were cultured on an immobilized matrix molecule overnight and the RNA was extracted, and then have found that their message was reduced by the anti-.beta.1 is considered that the matrix molecule will function as a co-stimulatory factor of lymphocytes.
The interaction between matrix molecule and cells will be participated by mainly integrin molecule and by other various molecules such as CD26 and CD44. Haynes et al. reported that adhesive molecules of VLA family exist widely in cells of synovial tissue such as Type A synovial cells, vessel (1989)!.
It is known that the adhesion molecules of the VLA family include VLA-1, -2, -3, -4, -5 and -6, in each of which the .beta.1 chain and a chain (.alpha.1, .alpha.2, .alpha.3, .alpha.4, .alpha.5, or .alpha.6) are non-covalently bound each other to form heterodimers, wherein .alpha.4 may also associate with .beta.7 and .alpha.6 may also associate with .beta.4, and hence, it will be understood that .alpha.4.beta.7 and .alpha.6.beta.4 also belong to VLA family.
DISCLOSURE OF THE INVENTION
The present inventors have studied the treatment of RA by utilizing a monocl
REFERENCES:
patent: 5583203 (1996-12-01), Hemler
Panayi, et al., "The Importance of the T Cell in Initiating and Maintaining the Chronic Synovitis of Rheumatoid Arthritis", Arth. Rheum., vol. 35, No. 7, 1992, pp. 729-735.
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Miyake Sachiko
Nishida Tadashi
Okumura Ko
Yagita Hideo
Johnson Nancy A.
Kanebo Ltd.
Scheiner Toni R.
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