JPS5821623A - Remedy for diseases caused by deposition of antigen- antibody complex - Google Patents

Abstract

PURPOSE:A remedy for systemic lupus erythematosus or primary glomerulonephritis that contains a gamma globulin having the Fc part. CONSTITUTION:A gamma globulin havin the Fc part, which is obtained by subjecting gamma globulin to chemical or enzymatic treatment causing no destruction of the Fc part, thus being injected for plasmin treatment, is used as an active ingredient to given a remedy for systemic lupus erythematosus or primary glomerulonephritis. It is given intravenously, the dose is 20-100mg/kg/day as gamma globulin and continued for one to several weeks. It seems that, when the globulin reaches the lesion site, excessive amounts of the Fc part bind with the deposite to cleave the bonds between antigen-antibody, resulting in dissolution of the deposit.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the treatment of diseases caused by the deposition of antigen-antibody complexes containing gamma globulin having an Fc portion as an active ingredient in cells and tissues, such as systemic lupus erythematosus and chronic -Related to new therapeutic agents for collagen diseases such as rheumatoid arthritis and primary glomerulonephritis.

Gamma globulin preparations are already commercially available as passive immunotherapeutic agents for the purpose of replacement therapy for primary immunodeficiency and combination therapy with antibiotics for prevention of viral infections and type 1 infections. discovered that gamma globulin having an Fc portion is extremely effective against diseases caused by the deposition of antigen-antibody complexes in cells or tissues, and completed the present invention.

Typical diseases caused by tissue or cell deposition of antigen-antibody complexes include systemic lupus erythematosus, collagen diseases such as rheumatoid arthritis, and primary glomerulonephritis.

For example, in glomerulonephritis, Ig is present on the glomerular capillary basement membrane.
The continuous presence of G and complement has been proven by fluorescence antibody blueprint analysis. In addition, in rheumatoid arthritis, degenerated 1gG
There is an autoantibody, rheumatoid factor, whose antigen is rheumatoid factor.
Arthritis develops through a series of reactions triggered by the binding and deposition of antigen-antibody complexes and complement within the joint.

Currently, the main treatments for these diseases are using adrenocortical hormones and immunosuppressants, but not only are these treatments not curative, but long-term use can cause serious side effects. It was hoped that a therapy could be developed.

In knee diseases triggered by the deposition of these antigen-antibody complexes, gamma globulin with an Fc portion is
For example, by intravenous administration, this complex dissolves or significantly disappears, and a radical therapy has been found by eliminating the cause of these diseases.

Gamma fist globulin having an Fc portion is a method for producing gamma globulin without destroying its Fc portion.
Refers to gamma globulin that has been subjected to appropriate treatments such as chemical or enzymatic treatment and can be injected intravenously.

Therefore, plasmin-treated injectable gamma globulin preparations, sulfonated injectable gamma globulin preparations (listed in the standards for biological products: dried sulfonated human immunoglobulin), or polyethylene glycol-treated injectable gamma globulin preparations, which are commercially available under the trade name of venoglobulin. A gamma globulin preparation (name listed in the Biological Products Standards: Dry polyethylene glycol-treated human immunoglobulin) is suitably used as the preparation of the present invention.

The preparations of the present invention are not limited to these commercially available preparations, but gamma globulin is treated with plasmin or chemically without destroying its FC portion, and then processed as necessary according to known manufacturing methods for injections. Depending on the situation, preparations prepared by adding stabilizers and preservatives such as glycine and methyl thiolate may also be used.

The effectiveness of the preparation of the present invention has been theorized from analysis of the etiology of these intractable diseases based on immunological theory, and the effectiveness of the present invention has been demonstrated in Examples. It is an innovative therapeutic agent that can be applied to various diseases caused by deposition.

The mechanism of action of the formulation of the present invention will be described below.

In the case of glomerulonephritis, antigen-antibody complexes are deposited in various locations in blood vessels, and are particularly deposited prominently on the renal glomerular capillary basement membrane. As a result, the complement system is activated and vasoactive amines are released. Furthermore, according to the findings of the present inventor,
The antigen-antibody complex itself binds to the antigen, and then the antibody (rheumatoid factor) binds to form larger deposits, resulting in the development of glomerulonephritis.

Gamma-containing Fc portion was administered intravenously to this lesion.
When the globulin arrives, the Fc portion binds excessively to the deposit, causing a change in the structure of the deposit, and the antigen-antibody bond in the deposit is cleaved.This causes the antigen-antibody complex to collapse, and the deposit It appears that dissolution occurs.

The route of administration of the formulation of the present invention is usually intravenous administration; Intramuscular or localized injections are also possible.

Dosage for antigen-antibody complex deposition disease is based on body weight IKg
The standard is to administer 20 to 100 g of gamma globulin per day or 1000 to 500 g of gamma globulin once a day for 1 to several weeks by intravenous administration, depending on the symptoms. may be used in combination.

The effect of the preparation of the present invention on dissolving antigen-antibody complex deposits will be described below.

Renal tissues were collected by renal biopsy from 3 patients with glomerulonephritis and 2 patients with systemic lupus erythematosus, and frozen section specimens with a thickness of 4 tones were made from these specimens. The test was conducted using Gamma globulin preparations for testing include commercially available plasmin-treated gamma globulin preparations for injection, sulfonated gamma globulin preparations for injection, polyethylene glycol-treated gamma globulin preparations for injection, and pepsin-treated injection gamma globulin preparations in which the Fc portion has been destroyed. A gamma globulin preparation (name listed in the standards for biological products: dried pepsin-treated human immunoglobulin) was used.

Each gamma globulin preparation for injection was dissolved in distilled water to give test solutions of 5%, 1%, and 0.1%, respectively. This test solution was added to each of the above section specimens, reacted for 1 hour, and then washed with phosphate buffer for 30 minutes.

This operation was repeated four more times. As a control, the above operation was performed using a phosphate buffer instead of the test solution.

When each section specimen was observed by fluorescent antibody method, extensive deposition of antigen-antibody complexes was observed in the renal glomerular basement membrane in the control group, but plasmin-treated gamma globulin solution for injection, sulfonated injection In the groups to which the gamma globulin preparation solution and the polyethylene glycol-treated gamma globulin preparation solution were added, no or almost no antigen-antibody complex deposition was observed at a total concentration of 0.1% from 5. On the contrary, in the group to which the pepsin-treated gamma globulin preparation solution was added, it was observed that widespread deposition of antigen-antibody complexes remained, as in the control group.

The clinical effects of the formulation of the present invention will be described below. Case 0-1: 45-year-old male. The chief complaints were proteinuria and edema, and a kidney biopsy diagnosed membranous nephritis. Human IgG and complement C3 were found deposited in coarse granules along the renal glomerular loop.

A commercially available plasmin-treated gamma globulin preparation for injection was administered intravenously at a dose of 2,500 μl once a day every day for three weeks. From 1 week after the start of administration, proteinuria and edema significantly improved. When the kidney was biopsied again three weeks later, the deposition of IgG and C3 in the renal glomerulus was clearly reduced, confirming the usefulness of this rule.

Example-2 A 30-year-old woman. The patient exhibited symptoms of facial erythema, proteinuria, and hair loss, typical findings of systemic lupus erythematous disease. Skin and kidney biopsies revealed granular deposits of IgG at the dermal-epithelial junction and renal glomerular loops.

In combination with an immunosuppressant, a commercially available plasmin-treated gamma globulin preparation for injection was administered intravenously once a day at a dose of 2,500 yen or more every day for 3 weeks. With this therapy, the skin clinical findings improved and proteinuria was no longer observed.

At the same time, IgG deposits in both the skin and renal glomeruli were almost completely disappeared in biopsies. No signs of recurrence have been observed for 6 months since the completion of this treatment.

Example-3 34 year old female. She developed joint pain and stiffness in her hands in the early morning.

In addition to the chief complaint, the patient had wrist deformity, and was diagnosed with rheumatoid arthritis according to the diagnostic criteria of the American Rheumatology Association. Approximately 6 months after the onset of symptoms, a commercially available plasmin-treated gamma globulin preparation for injection was administered intravenously once a day at a dose of 2,500 or more for 2 weeks, and a marked improvement in clinical symptoms was observed.

Patent Applicant Toru Sugisaki Three Agents Yoshiro Ishihara Procedural Amendment August 20, 1980 Commissioner of the Patent Office Kazuo Wakasugi 1, Indication of the Case 1982 Patent Application No. 118928 2, Title of Invention Antigen-antibody complex deposition Disease treatment agent 3. Relationship with the case of the person making the amendment Patent applicant name Toru Sugisaki 34, attorney 5, date of amendment order 8, content of amendment as attached.

Full text correction statement 1. Title of the Invention: Antigen-antibody complex deposition disease therapeutic agent 2. Claims: A therapeutic agent for systemic lupus erythematosus or primary glomerulonephritis, which contains gamma globulin having an Fc portion as an active ingredient.

3. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel therapeutic agent for systemic inflammatory disease or primary glomerulonephritis, which contains gamma globulin having 10 moieties as an active ingredient.

Gamma globulin preparations are already commercially available as passive immunotherapeutic agents for the purpose of replacement therapy for primary immunodeficiency, prevention of viral infections, and combination therapy with antibiotics for severe infections. The present invention was completed based on the discovery that gamma globulin having an Fc portion is extremely effective against systemic lupus erythematosus and primary glomerulonephritis, which are mainly caused by the deposition of antigen-antibody complexes in cells or tissues.

Currently, the main treatments for these diseases are using adrenocortical hormones and immunosuppressants, but not only are these treatments not curative, but long-term use can cause serious side effects. It was hoped that a therapy could be developed.

These diseases are thought to be triggered by the deposition of antigen-antibody complexes, and in these diseases, gamma globulin having 10 moieties can be administered intravenously, for example, to reduce this complex. This led to the discovery of a radical cure by eliminating the cause of these diseases.

Gamma globulin having an Fc portion refers to gamma globulin in a manner that does not destroy its Fc portion.
Refers to gamma globulin that has been subjected to appropriate treatments such as chemical or enzymatic treatment and can be injected intravenously.

Therefore, plasmin-treated injectable gamma globulin preparations, sulfonated injectable gamma globulin preparations (listed in the Biological Products Standards: Psoriasis sulfonated human immunoglobulin) or polyethylene glycol-treated injections are commercially available under the trade name of venoglobulin. A gamma globulin preparation (biological product standard registered name: dry polyethylene glycol-treated human immunoglobulin) is suitably used as the preparation of the present invention.

The preparations of the present invention are not limited to these commercially available preparations, but are prepared by subjecting gamma globulin to enzyme treatment or chemical treatment without destroying its Fc portion, and then subjecting the gamma globulin to enzyme treatment or chemical treatment, etc., according to known manufacturing methods for injections, as necessary. Depending on the situation, preparations prepared by adding stabilizers and preservatives such as glycine and methyl thiolate may also be used.

The effectiveness of the preparation of the present invention has been theorized from analysis of the etiology of these intractable diseases based on immunological theory, and the effectiveness of the present invention has been proven in clinical examples.
It is an innovative therapeutic agent that can be applied to these diseases.

The mechanism of action of the formulation of the present invention will be described below.

In primary glomerulonephritis, antigen-antibody complexes are deposited at various locations in blood vessels, particularly on the renal glomerular capillary basement membrane. As a result, the complement system is activated and vasoactive amines are released. Furthermore, according to the findings of the present inventors, the antigen-antibody complex itself becomes an antigen, and the antibody (
The binding of rheumatoid factor (rheumatoid factor) occurs, resulting in the formation of larger deposits and the development of primary glomerulonephritis.

Systemic lupus erythematosus disease is also thought to develop due to similar causes.

For example, when intravenously administered gamma globulin containing an Fc portion reaches this lesion, the Fc portion binds excessively to the deposit, causing a change in the structure of the deposit, and the antigen-antibody bond in the deposit is cleaved. However, this appears to cause the antigen-antibody complex to collapse and the deposit to dissolve.

The administration route for the preparation of the present invention is usually intravenous administration, but intramuscular or local injection into the affected area is also possible.

The dosage for these diseases is 20 to 100 gamma globulin per IKg of body weight or 100 gamma globulin per dose for adults.
The standard method is to administer 0 to 5,000 μl intravenously once a day, every day for several weeks. We will discuss the dissolution effect of antigen-antibody complex deposits.

Renal tissues were collected by renal biopsy from 3 patients with primary glomerulonephritis and 2 patients with systemic lupus erythematosus, and frozen section specimens with a thickness of 4 pm were made from these specimens. The test was conducted using

The gamma globulin preparation for testing was a commercially available plasmin-treated gamma globulin preparation for injection.

Sulfonated injectable gamma globulin preparations, polyethylene glycol-treated injectable gamma globulin preparations, and Fc
A partially destroyed pepsin-treated gamma globulin preparation for injection (biological product standard listing name: dried pepsin-treated human immunoglobulin) was used.

Each gamma globulin preparation for injection was dissolved in distilled water to make test solutions of 5%, 1%, and 11%.The test solutions were added to the section specimens prepared above, and after reacting for 1 hour, Washed with phosphate buffer.

This operation was repeated four more times. Also, as a contrast,
The above operation was performed using a phosphate buffer instead of the test solution.

When each section specimen was observed by fluorescent antibody method, extensive deposition of antigen-antibody complexes was observed on the renal glomerular basement membrane in the control group, but plasmin-treated comma globulin solution for injection, sulfonated injection In the groups to which the gamma globulin preparation solution and the polyethylene glycol-treated gamma globulin preparation solution were added, no or almost no deposition of antigen-antibody complexes was observed at all concentrations from 5% to 0.1%. On the contrary, in the group to which the pepsin-treated gamma globulin preparation solution was added, extensive deposition of antigen-antibody complexes remained, as in the control group, even in the group to which the 5% solution was added.

The clinical effects of the formulation of the present invention will be described below. Case 0-1: 45-year-old male. The chief complaints were proteinuria and edema, and a kidney biopsy diagnosed membranous nephritis. Human 1gG and complement Cs were found deposited in coarse granules along the renal glomerular loop.

A commercially available plasmin-treated gamma globulin preparation for injection was administered intravenously at a dose of 2,500 capes once a day every day for three weeks. From 1 week after the start of administration, proteinuria and edema significantly improved. When the kidney was biopsied again three weeks later, the deposition of human IgG and C8 in the renal glomerulus was clearly reduced, supporting the usefulness of the powder.

Example-2 A 30-year-old woman. The patient exhibited symptoms of facial erythema, proteinuria, and hair loss, typical findings of systemic lupus erythematous disease. Skin and kidney biopsies revealed granular deposits of human IgG at the dermal-epithelial junction and along the renal glomerular loops.

In combination with an immunosuppressant, a commercially available plasmin-treated injectable comma globulin preparation, 250011F, was administered intravenously once a day every day for three weeks. With this therapy, the skin clinical findings improved and proteinuria was no longer observed.

At the same time, IgG deposits in both the skin and renal glomeruli were almost completely disappeared in biopsies. No signs of recurrence have been observed for 6 months since the completion of this treatment.

Example-3 A 38-year-old woman. The chief complaints were proteinuria and edema, and a kidney biopsy diagnosed membranous nephritis.

5 doses of plasmin-treated injectable gamma globulin preparation
,000 sv was administered intravenously 8 times a week for 2 weeks.

As a result, proteinuria decreased significantly, and systemic edema, including stiffness of the hands, became milder and showed improvement.

Example-4 88 year old male. The patient's chief complaints were proteinuria and edema, and a kidney biopsy revealed membranoproliferative nephritis.

Plasmin-treated gamma globulin preparation for injection was administered intravenously at a dose of 5.00~3 times a week for a total of 8 times.As a result, proteinuria was significantly reduced and systemic symptoms were extremely improved.

Example-5 29 year old female. The patient presented with symptoms similar to those of the patient in Example 2, and findings of systemic lupus erythematous disease were observed.

5 doses of plasmin-treated injectable gamma globulin preparation
,000q was administered intravenously 4 times every other day.

Claims (1)

[Claims] A therapeutic agent for diseases caused by cell or tissue deposition of antigen-antibody complexes containing gamma globulin having an Fc portion as an active ingredient.