WO1992007583A1 - ANTI-UBIQUITIN IgG IN THE TREATMENT OF SYSTEMIC AMYLOIDOSIS - Google Patents
ANTI-UBIQUITIN IgG IN THE TREATMENT OF SYSTEMIC AMYLOIDOSIS Download PDFInfo
- Publication number
- WO1992007583A1 WO1992007583A1 PCT/CA1991/000398 CA9100398W WO9207583A1 WO 1992007583 A1 WO1992007583 A1 WO 1992007583A1 CA 9100398 W CA9100398 W CA 9100398W WO 9207583 A1 WO9207583 A1 WO 9207583A1
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- WO
- WIPO (PCT)
- Prior art keywords
- ubiquitin
- amyloidosis
- igg
- amyloid
- aef
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the invention relates to a method for treating reactive systemic amyloidosis.
- Reactive systemic amyloidosis designated as inflammation-associated AA amyloidosis is a severe and often a life threatening complication of rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA) and ankylosing spond litis (AS).
- RA rheumatoid arthritis
- JRA juvenile rheumatoid arthritis
- AS ankylosing spond litis
- AA amyloidosis usually appears after several years of rheumatoid arthritis with insidious proteinuria followed by nephrosis and hepato-splenomegaly.
- Renal amyloidosis without proteinuria has also been reported in RA, JRA and AS cases.
- amyloidosis secondary to RA, JRA and AS varies considerably in different biopsy and autopsy series. It has been estimated that the approximate frequency of amyloidosis in RA, determined from post-mortem series, is 14 to 26% and 5 to 11% based on biopsy series. Involvement of renal glomeruli with AA amyloid is basically an irreversible process and the prognosis of such patients is generally considered to be poor. Demonstration of amyloid deposits in biopsy or autopsy samples remains the most accepted criterion for amyloid associated complications in RA. There is no effective treatment for reactive or other forms of systemic amyloidosis.
- this method of treatment should not have any adverse effects on the CNS.
- a method for the treatment of amyloidosis which comprises administering to a patient suspected of suffering from amyloidosis, an effective amount of an anti-ubiquitin IgG antibody, thus blocking the amyloid enhancing factor activity of ubiquitin and therefore preventing further amyloid deposition in vulnerable target organs.
- amyloid enhancing factor is believed to be such a link. In fact, without the presence of a substantial tissue concentration of AEF, amyloid deposition does not occur. This indicates that AEF is the primary pathogenic factor involved in amyloidogenesis.
- AEF has been known for a long time, but its identification as ubiquitin has been discovered only recently. Based on the partial amino acid sequence homology, immunochemical and pathophysiological criteria, AEF activity in ubiquitin isolated from murine amyloidotic tissues has been recently identified. Results prove that ubiquitin isolated from AD brain extracts also has AEF activity and that both ubiquitin and AA amyloid (inflammation associated amyloid derived from serum amyloid A protein) codeposit in identical tissue sites in splenic perifollicular areas of mice undergoing accelerated amyloidogenesis. Furthermore, it has also been demonstrated that ubiquitin binds to AA amyloid deposits in murine tissues. This suggests a critical role for ubiquitin in amyloidogenesis.
- ubiquitin Intracellularly, ubiquitin is found either free in a monomeric form, or linked via its COOH terminal glycine residue to €-NH 2 groups of lysine residues of a variety of cytoplasmic, nuclear and cell surface proteins. It has been proposed that ubiquitin acts as a cofactor with non- lysosomal degradation and rapid turn-over of some short-lived and abnormal proteins. Previous studies indicate that ubiquitin targetted protein complex formation is mediated through ATP in which covalent bond formation occurs between e-NH 2 groups of lysines of proteins and COOH terminal glycine of ubiquitin. There is also experimental evidence which suggests that replacement of COOH terminal glycine group of monoubiquitin prevents the biological activity of ubiquitin.
- a method for the treatment of amyloidosis which comprises administering to a patient suffering from amyloidosis, an effective amount of an anti-ubiquitin antibody IgG.
- Alzheimer's disease Deterioration of memory and intellectual functions, e.g. Alzheimer's disease, are believed to be a direct outcome of amyloid deposition in certain target sites in the brain.
- the present invention could be applied for treating Alzheimer's disease with the use of a monoclonal anti-ubiquitin antibody produced by human hybridomas.
- an anti- ubiquitin IgG antibody can also be obtained by standard monoclonal antibody procedures. It should be noted that a monoclonal anti-ubiquitin antibody using human hybridomas will probably extend the clinical application of this antibody in the treatment of reactive amyloidosis and possibly Alzheimer's disease, if the antibody is produced by human hydridomas.
- RABU rabbit anti-bovine ubiquitin IgG
- bovine ubiquitin (BU; 3.8 mg; Sigma Chemical Co., MO, U.S A.) cross-linked to keyhole limpet hemocyanin (15 mg; Calbiochem, CA, U.S A.) with 80 ⁇ l of 3% glutaraldehyde was used as the antigen (1:1 with Freund's complete adjuvant) to immunize rabbits.
- the antiserum was incubated (overnight, 4 * C) with CNBr-activated Sepharose 4B (Pharmacia, Montreal, Canada) conjugated to BU (5 mg protein/ml gel) and the bound protein was eluted from the gel with 0.1 M glycine-HCl, pH 2.8.
- the eluted protein was dialyzed against 0.1 M sodium phosphate buffer pH 7.4, containing 0.5 M NaCl and passed through a Protein A- Sephrose gel column to elute RABU.
- RABU was dialyzed against 0.01 M phosphate buffer pH 7.4 containing 0.15 M NaCl (PBS) and their protein concentrations determined as described above.
- IgG from normal rabbit sera was purified using the conventional methods.
- RABU anti- ⁇ biquitin antibody
- Passively transferred specific antibody either through natural transmission such as mother to fetus through placenta or by way of clostrum, or artificial transmission by way of intramuscular or intravenous injection is known to afford protection against a number of bacterial infections, for example, diptheria, tetanus, pneumococcus, meningococcus and the like, viral infections and various antigenic proteins such as insects, snake venom and the like.
- passive immunization can be employed as a prophylactic measure.
- Interaction between ubiquitin and serum amyloid A protein, the precursor of AA amyloid, in the extracellular matrix is a prerequisite for the genesis of AA amyloid in vivo.
- results show that an effective concentration of anti-ubiquitin antibody in the peripheral circulation blocks the activity of extracellular amyloidogenic ubiquitin and thus abrogates the conversion of SAA into AA amyloid.
- mice In the first protocol, groups of C57BL/6J male mice (6/group) were injected i.p with various amounts of RABU. After 24 hrs, these mice were challenged with an amyloidogenic dosage of 0.2 mg of AEF protein (i.p) and 0.5 ml of 2% aqueous AgNO 3 (S.C). Cryostat congo red stained spleen sections from these mice were prepared 48 hr after the challenge injections. Control mice received a single dose of 5 mg normal rabbit IgG instead of RABU, and these mice were then challenged with 0.2 mg of AEF protein and 0.5 ml of 2% AgNO 3 solution.
- AEF protein i.p
- S.C aqueous AgNO 3
- an amyloidogenic dosage of 0.2 mg of AEF protein was incubated with known amounts of RABU (overnight, 4*C).
- the incubation mixture was microfuged (15000 rpm, 4*C, 15 min) and the supernatent was injected intraperitoneally along with 0.5 ml of 2% aqueous AgNO 3 subcutaneously.
- the spleen sections were processed as above.
- normal rabbit IgG instead of RABU was incubated with 0.2 mg of AEF protein and bioassayed as above.
- results presented in Tables 1 and 2 show that RABU, whether passively transferred 24 hours prior to challenge with crude AEF (Table 1), or injected after overnight incubation with crude AEF (Table 2), completely abolished the biological activity of crude AEF in a dose dependent manner.
- the optimal concentration of RABU required for complete abolition of splenic amyloidogenesis in the mice was approximately 2-fold higher in the antibody passive transfer experimental groups, than in that of overnight incubation with RABU.
- RABU is a polyclonal antibody against ubiquitin.
- polyclonal antibodies contain mixed populations of antibodies of varying specificities against an antigen.
- monoclonal anti-ubiquitin antibody using human hybridomas will have 3 clear benefits: first, it will be homogeneous; second, because of its strong, specificity against the functional ubiquitin epitope, a relatively smaller dosage will have therapeutic value in blocking the amyloidogenic activity of ubiquitin in vivo: and, thirdly, and most importantly, it will be relatively safe to have its clinical application in humans without the undesirable and serious outcome of interspecies immunological problems such as transfer of RABU to humans.
Abstract
The present invention consists of a method for the treatment of amyloidosis, more particularly systemic amyloidosis, which comprises administering to a patient suspected of suffering from amyloidosis, an effective amount of an anti-ubiquitin IgG antibody, thus blocking the amyloid enhancing factor activity of ubiquitin, and therefore preventing further amyloid deposition in vulnerable target organs.
Description
Anti-ubiquitin IgG in the treatment of systemic amyloidosis .
The invention relates to a method for treating reactive systemic amyloidosis.
PRIOR ART;
Reactive systemic amyloidosis, designated as inflammation-associated AA amyloidosis is a severe and often a life threatening complication of rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA) and ankylosing spond litis (AS).
AA amyloidosis usually appears after several years of rheumatoid arthritis with insidious proteinuria followed by nephrosis and hepato-splenomegaly. Chronic nephrotic syndrome and renal insufficiency, due to amyloid deposition in the kidney parenchyma, are common causes of death in such amyloidosis cases. Renal amyloidosis without proteinuria has also been reported in RA, JRA and AS cases.
The prevalence of amyloidosis secondary to RA, JRA and AS varies considerably in different biopsy and autopsy series. It has been estimated that the approximate frequency of amyloidosis in RA, determined from post-mortem series, is 14 to 26% and 5 to 11% based on biopsy series. Involvement of renal glomeruli with AA amyloid is basically an irreversible process and the prognosis of such patients is generally considered to be poor. Demonstration of amyloid deposits in biopsy or autopsy samples remains the most accepted criterion for amyloid associated complications in RA. There is no effective treatment for reactive or other forms of systemic amyloidosis.
Accordingly, there is a great need for a method of treatment of amyloidosis, or at least a method for retarding or slowing down amyloid deposition in target organs. Preferably, this method of treatment should not have any adverse effects on the CNS.
SUMMARY OF THE INVENTION;
In accordance with the present invention, there is now provided a method for the treatment of amyloidosis, which comprises administering to a patient suspected of suffering from amyloidosis, an effective amount of an anti-ubiquitin IgG
antibody, thus blocking the amyloid enhancing factor activity of ubiquitin and therefore preventing further amyloid deposition in vulnerable target organs.
DETAILED DESCRIPTION OF THE INVENTION;
Structural studies on purified amyloid proteins indicate at least 10 different chemical forms of human amyloids. The sharing of a number of common physical, chemical and staining characteristics by all amyloids suggests that there may be a common pathogenic factor in all forms of amyloidosis. The amyloid enhancing factor (AEF) is believed to be such a link. In fact, without the presence of a substantial tissue concentration of AEF, amyloid deposition does not occur. This indicates that AEF is the primary pathogenic factor involved in amyloidogenesis.
AEF has been known for a long time, but its identification as ubiquitin has been discovered only recently. Based on the partial amino acid sequence homology, immunochemical and pathophysiological criteria, AEF activity in ubiquitin isolated from murine amyloidotic tissues has been recently identified. Results prove that ubiquitin isolated from AD brain extracts also has AEF activity and that both ubiquitin and AA amyloid (inflammation associated amyloid derived from serum amyloid A protein) codeposit in identical tissue sites in splenic perifollicular areas of mice undergoing accelerated amyloidogenesis. Furthermore, it has also been demonstrated that ubiquitin binds to AA amyloid deposits in murine tissues. This suggests a critical role for ubiquitin in amyloidogenesis.
Prior work on ubiquitin (Perry et aL Proc. Natl. Acad. Sci. U.SA.,
1987. 84. 3033) has shown that ubiquitin is found in association with highly insoluble neurofibrillary tangles (NFT) present both in tracellularly in dystrophic neurones and in senile plaques in the brain. However, neither the role of ubiquitin in the genesis of NFT nor the quantitative aspect of ubiquitin related to Alzheimer's disease is described or mentioned.
Intracellularly, ubiquitin is found either free in a monomeric form, or linked via its COOH terminal glycine residue to €-NH2 groups of lysine residues of a variety of cytoplasmic, nuclear and cell surface proteins.
It has been proposed that ubiquitin acts as a cofactor with non- lysosomal degradation and rapid turn-over of some short-lived and abnormal proteins. Previous studies indicate that ubiquitin targetted protein complex formation is mediated through ATP in which covalent bond formation occurs between e-NH2 groups of lysines of proteins and COOH terminal glycine of ubiquitin. There is also experimental evidence which suggests that replacement of COOH terminal glycine group of monoubiquitin prevents the biological activity of ubiquitin.
In accordance with the present invention, there is now provided a method for the treatment of amyloidosis, which comprises administering to a patient suffering from amyloidosis, an effective amount of an anti-ubiquitin antibody IgG.
Deterioration of memory and intellectual functions, e.g. Alzheimer's disease, are believed to be a direct outcome of amyloid deposition in certain target sites in the brain. Amyloid deposits involving cerebral blood vessels and the core of senile plaques, along with the generation of neurofibrillary tangles in selected cortical regions in the brain, are the cardinal lesions in Alzheimer's disease. By analogy, the present invention could be applied for treating Alzheimer's disease with the use of a monoclonal anti-ubiquitin antibody produced by human hybridomas.
The method for the generation of rabbit anti-bovine ubiquitin IgG antibody is described in the Examples.
Although the antibody discussed in the present invention was obtained through standard polyclonal procedures, it is to be appreciated that an anti- ubiquitin IgG antibody can also be obtained by standard monoclonal antibody procedures. It should be noted that a monoclonal anti-ubiquitin antibody using human hybridomas will probably extend the clinical application of this antibody in the treatment of reactive amyloidosis and possibly Alzheimer's disease, if the antibody is produced by human hydridomas.
It will be appreciated that the actual preferred dosages of anti- ubiquitin antibody in a specific case will vary according to the clinical form of amyloidosis.
The following Examples are provided to illustrate the present invention rather than limit its scope.
EXAMPLE 1
Antibody
The method for the generation of rabbit anti-bovine ubiquitin IgG (RABU) is as follows: bovine ubiquitin (BU; 3.8 mg; Sigma Chemical Co., MO, U.S A.) cross-linked to keyhole limpet hemocyanin (15 mg; Calbiochem, CA, U.S A.) with 80 μl of 3% glutaraldehyde was used as the antigen (1:1 with Freund's complete adjuvant) to immunize rabbits. The antiserum was incubated (overnight, 4 * C) with CNBr-activated Sepharose 4B (Pharmacia, Montreal, Canada) conjugated to BU (5 mg protein/ml gel) and the bound protein was eluted from the gel with 0.1 M glycine-HCl, pH 2.8. The eluted protein was dialyzed against 0.1 M sodium phosphate buffer pH 7.4, containing 0.5 M NaCl and passed through a Protein A- Sephrose gel column to elute RABU. RABU was dialyzed against 0.01 M phosphate buffer pH 7.4 containing 0.15 M NaCl (PBS) and their protein concentrations determined as described above. For control experiments IgG from normal rabbit sera was purified using the conventional methods.
EXAMPLE 2
Effect of anti-υbiquitin antibody (RABU) on the "in vivo" amyloidogenic activity of crude AEF
Passively transferred specific antibody either through natural transmission such as mother to fetus through placenta or by way of clostrum, or artificial transmission by way of intramuscular or intravenous injection is known to afford protection against a number of bacterial infections, for example, diptheria, tetanus, pneumococcus, meningococcus and the like, viral infections and various antigenic proteins such as insects, snake venom and the like. In certain circumstances passive immunization can be employed as a prophylactic measure.
Interaction between ubiquitin and serum amyloid A protein, the precursor of AA amyloid, in the extracellular matrix is a prerequisite for the genesis of AA amyloid in vivo. In the mouse model of accelerated AA amyloidosis, results show that an effective concentration of anti-ubiquitin antibody in the peripheral circulation blocks the activity of extracellular amyloidogenic ubiquitin and thus abrogates the conversion of SAA into AA amyloid.
Two methods were used for assessing the blocking activity of RABU on amyloidogenesis.
In the first protocol, groups of C57BL/6J male mice (6/group) were injected i.p with various amounts of RABU. After 24 hrs, these mice were challenged with an amyloidogenic dosage of 0.2 mg of AEF protein (i.p) and 0.5 ml of 2% aqueous AgNO3 (S.C). Cryostat congo red stained spleen sections from these mice were prepared 48 hr after the challenge injections. Control mice received a single dose of 5 mg normal rabbit IgG instead of RABU, and these mice were then challenged with 0.2 mg of AEF protein and 0.5 ml of 2% AgNO3 solution.
In the second protocol, an amyloidogenic dosage of 0.2 mg of AEF protein was incubated with known amounts of RABU (overnight, 4*C). The incubation mixture was microfuged (15000 rpm, 4*C, 15 min) and the supernatent was injected intraperitoneally along with 0.5 ml of 2% aqueous AgNO3 subcutaneously. The spleen sections were processed as above. For control purposes, as indicated above, normal rabbit IgG instead of RABU was incubated with 0.2 mg of AEF protein and bioassayed as above.
Results presented in Tables 1 and 2 show that RABU, whether passively transferred 24 hours prior to challenge with crude AEF (Table 1), or injected after overnight incubation with crude AEF (Table 2), completely abolished the biological activity of crude AEF in a dose dependent manner. The optimal concentration of RABU required for complete abolition of splenic amyloidogenesis in the mice was approximately 2-fold higher in the antibody passive transfer experimental groups, than in that of overnight incubation with RABU. These results further confirm that AEF activity lies within ubiquitin and that RABU specifically
blocks the amyloidogenic activity of AEF. In the same manner as for crude AEF, RABU also blocked the amyloidogenic activity of purified ubiquitin.
These results clearly indicate that RABU blocks the functional group of ubiquitin involved in processing the soluble amyloid precursor protein into insoluble fibrillar amyloid deposits. The data presented in Table 1 clearly show that a dosage of 200 mg/kg body weight of RABU effectively blocked the biological activity of AEF; one out of 6 mice was positive for amyloid and 3% of the splenic follicle in the positive mouse contained small focal deposits of AA amyloid (Table 1, group 3).
It should be noted that RABU is a polyclonal antibody against ubiquitin. In general, polyclonal antibodies contain mixed populations of antibodies of varying specificities against an antigen. As indicated, monoclonal anti-ubiquitin antibody using human hybridomas will have 3 clear benefits: first, it will be homogeneous; second, because of its strong, specificity against the functional ubiquitin epitope, a relatively smaller dosage will have therapeutic value in blocking the amyloidogenic activity of ubiquitin in vivo: and, thirdly, and most importantly, it will be relatively safe to have its clinical application in humans without the undesirable and serious outcome of interspecies immunological problems such as transfer of RABU to humans.
* various amounts of RABU or NRG were injected intraperitonally into mice and 4 hrs later they were challenged with crude AEF (0.2 mg protein).
TABLE 2
Effect of in vitro incubation of rabbit anti-bovine ubiquitin IgG (RABU. or normal rabbit IgG (NRG) on amyloid enhancing factor activity of crude AEF (0.2 mg protein) *
Group
3
4
* various amounts of RABU or NRG were incubated overnight at 4 • C with crude murine AEF (0.2 mg protein) and the resulting supematants tested for AEF activity.
Claims
1. A method for the treatment of amyloidosis which comprises administering to a patient suspected of suffering from amyloidosis an effective amount of an anti-ubiquitin IgG antibody, thereby blocking the amyloid enhancing factor activity of ubiquitin and preventing amyloid deposition in target organs.
2. A method according to claim 1, wherein the anti-ubiquitin IgG antibody is a rabbit anti-bovine ubiquitin IgG.
3. A composition for treating amyloidosis which comprises an effective amount of an anti-ubiquitin IgG antibody, in association with a pharmaceutically acceptable carrier.
4. A composition according to claim 3, wherein the anti-ubiquitin
IgG antibody is a rabbit anti-bovine ubiquitin IgG.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60918290A | 1990-11-02 | 1990-11-02 | |
| US609,182 | 1990-11-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992007583A1 true WO1992007583A1 (en) | 1992-05-14 |
Family
ID=24439687
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA1991/000398 WO1992007583A1 (en) | 1990-11-02 | 1991-11-04 | ANTI-UBIQUITIN IgG IN THE TREATMENT OF SYSTEMIC AMYLOIDOSIS |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU8755191A (en) |
| WO (1) | WO1992007583A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140308297A1 (en) * | 2005-08-25 | 2014-10-16 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Stem Cell Fusion Model of Carcinogenesis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990012806A1 (en) * | 1989-04-26 | 1990-11-01 | Neosystem S.A. | Synthetic peptides of the conjugate of ubiquitine and histone h2a |
-
1991
- 1991-11-04 AU AU87551/91A patent/AU8755191A/en not_active Abandoned
- 1991-11-04 WO PCT/CA1991/000398 patent/WO1992007583A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990012806A1 (en) * | 1989-04-26 | 1990-11-01 | Neosystem S.A. | Synthetic peptides of the conjugate of ubiquitine and histone h2a |
Non-Patent Citations (4)
| Title |
|---|
| Dialog Information Services, File 155, Medline, accession no. 06862413, Manetto V et al: "Selective presence of ubiquitin in intracellular inclusions", & Am J Pathol (UNITED STATES) Mar 1989, 134 (3) p505-13 * |
| Dialog Information Services, File 155, Medline, accession no. 07145306, Dickson DW et al: "Diffuse Lewy body disease: light and electron microscopic immunocytochemistry of senile plaques", & Acta Neuropathol (Berl) 1989, 78 (6) p572-84 * |
| Dialog Information Services, File 155, Medline, accession no. 07196454, Tabaton M et al: "The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition", & Ann Neurol Dec 1989, 26 (6) p771-8 * |
| Dialog Information Services, Medline, accession no. 07317577, Dickson DW et al: "Ubiquitin immunoelec- tron microscopy of dystrophic neurites in cerebellarsenile plaques of Alzheimer's disease", & Acta Neuropathol (Berl) (GERMANY; WEST) 1990, 79 (5) p486-93 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140308297A1 (en) * | 2005-08-25 | 2014-10-16 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Stem Cell Fusion Model of Carcinogenesis |
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| Publication number | Publication date |
|---|---|
| AU8755191A (en) | 1992-05-26 |
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