JPH10259140A - Tumor necrotizing factor production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor useful for treatment of dyscrasia, septicemia, multiple organ failure, etc., by including anti-selektin antibody or sugar binding with the selektin. SOLUTION: The objective preparation is obtained by formulating anti- selektin antibody (anti-P-selektin antibody, e.g. mouse anti-human-P-selektin monoclonal antibody PB1.3) or a sugar binding with the selektin (sialyl-Lewis X and sialyl-Lewis X derivative, Lewis X and Lewis X derivative, especially preferably the one including α1,3-fucosylated α2,3-sialated lactosaminoglycan structure) with a conventional pharmaceutical carrier and an auxiliary material. The objective preparation is used for treating or preventing a disease, the appearance of which is considered to be corresponding to TNF through a production inhibition of the TNF by the sugar. An daily dose of the objective preparation is generally about 0.5mg-2000mg per patient of 70kg body weight.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a tumor necrosis factor production inhibitor.

[0002]

2. Description of the Related Art Tumor necrosis factor
(Hereinafter abbreviated as TNF) is a peptide composed of 157 amino acids and having a molecular weight of about 17,000, and is one of cytokines produced from various cells including macrophages.

[0003] TNF is a cytokine that fundamentally supports immune, inflammation, and biological defense responses. It is located not only upstream of the cytokine cascade but also in cytokines and endocrine hormones involved in maintaining homeostasis of various cells. Releases soluble factors such as reactive oxygen species (Clinical Immunity, 27 (S
uppl. 16), 259-268 (1995)). Its effects are diverse biological activities ranging from antitumor activity, antimicrobial activity, inflammation, tissue repair, stimulation of the immune system to physiological functions such as appetite, fever, sleep, and regulation of hormone secretion.

On the other hand, it has also been revealed that continuous or overproduction of TNF, on the contrary, has a severe effect on normal cells and causes various disease states. For example, TNF
Has been reported to be the same substance as cachectin, a inducer of cachexia in cancer and infectious diseases, which promotes catabolic metabolism in the whole body and causes extreme exhaustion (Beutler et al.)
al., Nature, 316, 552-554 (1985), Masayoshi Kawakami, Biochemistry,
59, 1244-1247 (1987)). In addition, anti-T
An inhibitory effect has been observed by using the NF antibody (see, for example, Starnes et al., J. Immunol. 145, 4185-4191 (1.
990)). Furthermore, in rheumatoid arthritis, an increase in TNF has been observed in synovial fluid and blood of patients (Tett).
a et al., Ann.Rheum.Dis., 49, 665-667, (1990)
).

[0005] In addition, Kawasaki disease (Matsubara et al., Cli
n. Immunol. Immunopathol., 56, 29-36 (1990)), ulcerative colitis (Murch et al., Arch. Dis. Child, 66, 561).
(1991)), Behcet's disease (Akoglu et al., J. Rheuma
tol., 17, 1107-1108 (1990)), systemic lupus erythematosus (S
LE) (Maury et al., Arthritis Rheum., 32, 146-15)
0 (1989)), rejection during bone marrow transplantation (GvHD) (J. E.
xp. Med., 175, 405-413 (1992)), multiple organ failure (Toshifumi Fujiwara et al., clinician 17 (10), 2006-2008 (1991)), malaria (Grau et al., Science, 237, 1210) -1212 (1987)),
Acquired Immunodeficiency Syndrome (AIDS) (Masawa Kawakami et al., Medi
cal Immunology, 20, 615-620 (1990)), meningitis (Waag
e et al., Lancet I, 355-357 (1987)), fulminant hepatitis (Kozo Sugano, liver, 33, 213-218 (1992)), bowl disease (Masahiro Maeda, Gastrointestinal and immunity, 22, 111-) 114 (1989))
There are many diseases for which the involvement of F is suggested.

As described above, it has been found that excessive TNF production sometimes has an adverse effect on living organisms, and research and development of TNF inhibitors that can be used as therapeutic agents for such pathological conditions are desired.

By the way, P-selectin, E-selectin and L-selectin which is constantly present on leukocytes (J.
Immunol. 143, 3318 (1989)) binds to its ligand, sialyl Lewis X sugar chain, to adhere leukocytes to endothelial cells and induce migration and infiltration of leukocytes into inflammatory sites (J. Cell Biol. 117, 895 (1992)), these accumulated leukocytes release various cytotoxic factors, causing cytotoxicity and tissue damage.

[0008] Cytokines such as IL-1, TNF and the like are attached to vascular endothelial cells by P-selectin (Biochem. Biop.
hys. Res. Commun. 210, 174-180 (1995)) and E-selectin (Science 243, 1160-1165 (1989)). Thus, it is known that TNF stimulation induces selectin expression induction. However, reports on the TNF production inhibitory effect of a substance that binds to and inhibits the above-mentioned selectin report that sulfatide (sulfate ester of lipid), which is a ligand of L-selectin and P-selectin, was found to be present in blood in a mouse endotoxin shock model. It has only been reported that the increase in TNF was suppressed (Record of the General Meeting of the Immunological Society of Japan, Academic Meeting, Vol. 26, 1P3-48 (1996)).

[0009]

DISCLOSURE OF THE INVENTION The present invention provides a TNF production inhibitor, and furthermore, a disease in which TNF is considered to be involved in the onset, for example, cachexia, sepsis, multiple organ failure, chronic joint disease. Rheumatism, ulcerative colitis, Behcet's disease, systemic lupus erythematosus (SLE), rejection during bone marrow transplantation (GvHD), multiple organ failure, malaria, acquired immunodeficiency syndrome (AIDS), meningitis, fulminant It provides a remedy for hepatitis, bowl disease and the like.

[0010]

Means for Solving the Problems The present inventors have found that a selectin inhibitor has a TNF production inhibitory activity, and have completed the present invention.

More specifically, in a lung injury model induced by an immune complex, it has been found that a selectin inhibitor suppresses the TNF concentration in bronchoalveolar lavage fluid collected by bronchoalveolar lavage. Bronchoalveolar lavage (bronchoalveola
r lavage (BAL) is a method of collecting a certain amount of fluid after injecting it into the sub-segment of the lung for the purpose of collecting cells and proteins present on the epithelial surface of the lower respiratory tract and alveoli. By analyzing the collected bronchoalveolar lavage fluid, the state of inflammation or immunity occurring in the lower respiratory tract and alveoli can be revealed. In clinical practice, it is performed as part of a bronchial fiberscope test that is currently performed as a routine test.

The gist of the present invention is as follows. (1) A tumor necrosis factor production inhibitor comprising an anti-selectin antibody or a sugar that binds to selectin as an active ingredient. (2) The tumor necrosis factor production inhibitor according to the above (1), wherein the anti-selectin antibody is an anti-P-selectin antibody. (3) The tumor necrosis factor production inhibitor according to the above (1), wherein the sugar that binds to the selectin is a sugar containing a sialyl Lewis X structure.

The term "anti-selectin antibody" means an immunoglobulin that recognizes selectin and selectively binds to selectin, thereby suppressing adhesion between cells. Preferably, it is an anti-P-selectin antibody. This antibody may be a polyclonal antibody or a monoclonal antibody. The origin of the antibody is not limited, and includes antibodies of mouse, rat or human origin. In addition, a chimeric antibody in which both human and mouse antibodies are partially bound, or a humanized antibody may be mentioned as an example. Specifically, an anti-P-selectin antibody
PB1.3 (WO93 / 21956) and anthropomorphic anti-P-selectin antibody PB1.3 (WO94 / 25067).

The sugars that bind to selectins include oligosaccharides that are ligands for selectins and derivatives thereof. Oligosaccharides and derivatives thereof include sialyl Lewis X and sialyl Lewis X derivatives,
Lewis X and Lewis X derivatives. Especially,
A sugar containing an α1,3-fucosylated or α2,3-sialylated lactosaminoglycan structure is preferred. Specifically, WO91 / 19501,
Sugars described in WO91 / 19502, WO94 / 26760 and WO96 / 20204 can be mentioned.

The anti-selectin antibody and the sugar binding to the selectin suppress TNF production in a rat immune complex-induced disorder model as described below. This indicates that the anti-selectin antibody and the sugar that binds to the selectin can treat a disease in which TNF is considered to be involved in the onset through the TNF production inhibitory action. The TNF production inhibitor of the present invention is administered parenterally, topically, orally, or transdermally, and can be administered in various unit dosage forms depending on the administration method. For example, unit dosage forms suitable for oral administration include powders, tablets, pills, capsules and dragees. The TNF production inhibitor of the present invention is administered, for example, intravenously. For intravenous administration, the drug is dissolved or suspended in a pharmaceutically acceptable carrier, preferably an aqueous carrier. As the aqueous carrier, for example, water, buffered water, physiological saline, and the like can be used. The resulting aqueous solutions can be packaged as is or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The therapeutic agent of the present invention may be a pharmaceutically acceptable auxiliary agent such as a pH adjusting agent and a buffer, a tonicity adjusting agent, an infiltrating agent and the like, for example, sodium acetate, sodium lactate, etc. Potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate and the like can be included.

The TNF production inhibitor of the present invention is administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The dosage of the TNF production inhibitor of the present invention varies depending on, for example, the specific active ingredient, the administration method, the degree of the disease to be treated, the overall health and condition of the patient, and the prescribing physician. About the patient,
About 0.5 mg to about 2 mg of the TNF production inhibitor of the present invention per day
000 mg, preferably for a patient weighing 70 kg, from about 5 mg to about 500 mg of active ingredient per day per day.
Use a dose in the range of mg. The TNF production inhibitor of the present invention can also be used as a prophylactic agent. In prophylactic applications, the TNF production inhibitors of the present invention are administered to patients who are susceptible to or otherwise at risk of a particular disease.

[0017]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention. In the following examples, mouse anti-human P-selectin monoclonal antibody PB1.3 (antibody described in WO93 / 21956) and mouse anti-rat P-selectin monoclonal antibody ARP2-4 (Glyco
biology 6 (4), 463-469 (1996)). A sialyl Lewis X derivative known as a selectin ligand (hereinafter, SLeX derivative) was used as a sugar that binds to selectin. The compound name of the present SLeX derivative is ethyl (5-acetamido-3,5-dideoxy-α-D-glycero-D-
Galact-2-nonulopyranosylic acid)-(2-3) -O- (β-D-galactopyranosyl)-(1-4) -O- [α-L-fucopyranosyl- (1
-3) -O]-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-(1-3) -O-β-D-galactopyranoside sodium salt, a known method (US Patent No. 5,576,30
No. 5).

Example Effect on cytokines in bronchoalveolar lavage fluid of rats in which lung injury was induced by the immune complex (Experimental method) Pentobarbital sodium was administered to male Long Evans male rats and anesthetized. After administration of an anti-BSA (bovine serum albumin) antibody from the bronchi, BSA was administered from the tail vein (positive control group). The negative control group received saline instead of BSA. Four hours later, bronchoalveolar lavage was performed with saline, and bronchoalveolar lavage fluid (bron
choalveolar lavage fluid: BALF)
After the BALF was centrifuged, the TNF concentration of the supernatant was measured. TN
The F concentration was measured using a TNF measurement kit (Genzyme). Anti-P-selectin antibody PB1.3 at a dose of 5 mg / kg
P2-4 was administered intravenously immediately before BSA administration at a dose of 2 mg / kg.
The SLeX derivative was administered intravenously at a dose of 30 mg / kg immediately before BSA administration. The results are shown in FIGS. 1, 2 and 3.

(Experimental Results) In the positive control group, an increase in the TNF concentration in the bronchoalveolar lavage fluid was observed as compared with the negative control group. PB1.3 administration group, ARP2-4 administration group or SLeX
The derivative administration group suppressed the increase in TNF concentration.

[Brief description of the drawings]

FIG. 1 shows the T of BALF in a rat immune complex-induced lung injury model.
Effect of anti-P-selectin antibody PB1.3 on NF concentration

FIG. 2: T of BALF in a rat immune complex-induced lung injury model
Effect of anti-P-selectin antibody ARP2-4 on NF concentration

FIG. 3. T of BALF in a rat immune complex-induced lung injury model
Effect of SLeX derivative on NF concentration

Claims (3)

[Claims] 1. A tumor necrosis factor production inhibitor comprising an anti-selectin antibody or a sugar that binds to selectin as an active ingredient. 2. The tumor necrosis factor production inhibitor according to claim 1, wherein the anti-selectin antibody is an anti-P-selectin antibody. 3. The tumor necrosis factor production inhibitor according to claim 1, wherein the sugar that binds to the selectin is a sugar containing a sialyl Lewis X structure.