Oncostatin M antagonists

Details Oncostatin M antagonists Oncostatin M antagonists

1999-03-25

2004-03-16

Chan, Christina (Department: 1644)

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Binds antigen or epitope whose amino acid sequence is...

C424S184100, C424S278100

Reexamination Certificate

active

06706266

ABSTRACT:

The present invention relates to the use of an antagonist of OSM in the manufacture of a medicament for the treatment or prophylaxis of an inflammatory arthropathy or inflammatory disorder and methods of screening for such antagonists.
Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects articular joints, characterised by synovial hyperplasia and extensive cellular infiltration by mononuclear cells and polymorphonuclear leukocytes(PMN). A complex, and poorly understood interplay between resident and infiltrating cell types leads to the chronic secretion of metalloproteinases(MMPs), resulting in destruction of articular cartilage, ligaments and subchondral bone (Firestein G S Current Opinion in Rheumatology. 4:348-54, 1992). Among the numerous pro-inflammatory cytokines implicated in driving RA joint pathology, TNF&agr; has been shown to play a pivotal role, with anti-TNF&agr; therapies showing clear benefit (Elliott M J. et al. Lancet. 344(8930):1105-10, 1994). TNF&agr; mediates several pathologic effects including induction of MMPs (Dayer J M. et al Journal of Experimental Medicine. 162(6):2163-8, 1985), upregulation of other pro-inflammatory cytokines (Haworth C. et al. European Journal of Immunology. 21(10):2575-9, 1991 and Dinarello C A. et al. Journal of Experimental Medicine.163(6):1433-50, 1986) and increased PMN adhesion and transendothelial cell migration(Smart S J. Casale T B American Journal of Physiology. 266:L238-45, 1994). Though TNF&agr; is viewed currently as the initiator of the pro-inflammatory cytokine cascade, relatively little is known of its positive regulation (Feldmann M. et al. Annual Review of Immunology. 14:397-440, 1996).
Oncostatin M (OSM) (Rose T M. Bruce A G. PNAS USA 88(19):8641-5, 1991) is a 28 kDa glycoprotein which belongs to a family of cytokines comprising IL-6, IL-11, leukaemia inhibitory factor (LIF), cililiary neurotrophic factor (CNTF) and cardiotrophin 1 (CT-1)(Taga T. Kishimoto T. Annual Review of Immunology. 15:797-819, 1997). All members share a common signalling chain, gp130, as part of a complex family of hetero- and homodimeric receptors (Grotzinger J. et al. [Article] Proteins. 27(1):96-109, 1997). OSM shares a common heterodimeric receptor with LIF, (LIFr: gp130, type I) and also has its own unique receptor comprising OSMr&bgr; chain and gp130 (type II) (Mosley B. et al. [Article] Journal Of Biological Chemistry. 271(51):32635-32643, 1996). OSM has long been known for effects on cell growth and differentiation (Horn D. et al [Journal Article]Growth Factors. 2(2-3):157-65, 1990). Recently, OSM has also been shown to have potent, pro-inflammatory properties in mice in vivo (Modur V. et al. J. Clin Invest. 100:158-168, 1997) and demonstrates potent synergy with IL-1 to promote articular cartilage degradation in model systems, ex-vivo (Cawston T. Biochemical & Biophysical Research Communications. 215(1):377-85, 1995).
OSM induces a prolonged increase in P-selectin (and E-selectin) in endothelial cells (Yao L. et al. Journal Of Experimental Medicine. 184(1):81-92, 1996), stimulates urokinase-type plasminogen activator activity in human synovial fibroblasts (Hamilton J. et al Biochemical & Biophysical Research Communications. 180(2):652-9, 1991) and is a powerful inducer of IL-6 from endothelial cells(Brown Tj.et al. Journal Of Immunology. 147(7):2175-80, Oct. 1, 1991). OSM has recently been measured in RA but not OA synovial fluid (Hui W. et al. Annals Of The Rheumatic Diseases. 56(3):184-187, 1997) and synovium, production of which has been localised to macrophages (1 997, Okamoto H et al. Arthritis and Rheumatism 40(6): 1096-1105) and Cawston et al (1998, Arthritis and Rheumatism, 41(10) 1760-1771). To-date further experiments in this field have been speculative based on the similarity of the IL-6 subfamily members (Carroll G. et al Inflamm. Res. 47 (1998) 1-7).
The present inventors have discovered that OSM has the ability to induce TNF&agr; secretion in macrophages. Contrary to recent data suggesting that OSM upregulates production of tissue inhibitor of metalloproteinase-1 (TIMP-1) (Nemoto et al 1996, A&R 39(4), 560-566), which complexes with and inactivates MMP-1 and would therefore be expected to decrease collagen release, the inventors discovery that OSM induces TNF&agr; secretion suggested to them that OSM may actually play a role in mediating cartilage destruction. Based on this discovery, the present inventors have demonstrated that therapeutic administration of a neutralising anti-OSM antibody without inhibition of other IL-6 family members can alone ameliorate collagen-induced arthritis in a mouse model. Synergy of OSM with TNF&agr; to promote collagen release from cartilage has subsequently been shown by T. Cawston et al (1998, Arthritis and Rheumatism, 41(10) 1760-1771).
According to the present invention there is therefore provided the use of an antagonist of OSM in the manufacture of a medicament for the treatment or prophylaxis of an inflammatory arthropathy or inflammatory disorder. A particular use of an antagonist of OSM is in the manufacture of a medicament to prevent or reduce collagen release from cartilage. The invention further provides a method for the treatment or prophylaxis of an inflammatory arthropathy or inflammatory disorder comprising administering an effective amount of an antagonist of OSM to a patient suffering from such a disorder.
The antagonist may function by blocking OSM from interaction with the OSM receptor gp130, or the other OSM receptors, OSMr&bgr; chain or LiFr, or by blocking formation of heterodimers of these proteins, and as such prevent OSM binding and signalling thereby reducing synthesis of pro-inflammatory cytokines and/or MMPs. The antagonist according to the invention may therefore be a ligand for either OSM or one or more of the OSM receptors (gp130, OSMr&bgr; or LIFr) or an agent capable of interfering with these interactions in a manner which affects OSM biological activity. Hereinafter reference to an antagonist to OSM can be taken to mean either an antagonist to OSM itself or to one of its receptors.
The present inventors have also demonstrated that in rheumatoid artritis synovial vascular endothelium, P and E-selectin co-localise with gp130, the sionalling element of type I and II OSM receptors. Without wishing to be bound by theory this indicates that OSM, produced by synovial macrophages might prime RA vascular endothelium to facilitatc leucocyte recruitment via upregulation of P and E-selectin. The finding that ligation of L-selectin by either specific antibody or fucoidan (L-selectin agonist) drives human mononuclear cells to secrete OSM may be highly significant in terms of amplification of the inflammatory response, by providing an additional local source of OSM to drive TNF&agr; and P and E-selectin.
Amino acid residues which are important for OSM's interaction with gp130 have been identified. From the published amino acid sequence of OSM (Malik et al., 1989, Mol. Cell Biol., 9(7), 2847-53, DNA sequence entry M27288 in EMBL database, protein sequence entry P13725 in Swissprot) these are G120, Q16 and Q20; N123 and N124 may also play a part (see SEQ ID. 12 and below). The first 25 residues are a signal peptide, and the mature protein begins at the sequence AAIGS. (SEQ ID NO: 13). The sequence is numbered from the first amino acid of the mature protein as shown.
SEQ ID 12
                             1   5           15          25          35
MGVLLTQRTL  LSLVLALLFP  SMASMAAIGS  CSKEYRVLLG  QLQKQTDLMQ  DTSRLLDPYI

         45          55   &ems

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