EP0214265A1 - Antigens, antibodies and their uses - Google Patents

Antigens, antibodies and their uses

Info

Publication number
EP0214265A1
EP0214265A1 EP86901937A EP86901937A EP0214265A1 EP 0214265 A1 EP0214265 A1 EP 0214265A1 EP 86901937 A EP86901937 A EP 86901937A EP 86901937 A EP86901937 A EP 86901937A EP 0214265 A1 EP0214265 A1 EP 0214265A1
Authority
EP
European Patent Office
Prior art keywords
antigen
candidosis
serum
human
antigens
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP86901937A
Other languages
German (de)
French (fr)
Inventor
Selby John Starkie
Gwynfor Rees Williams
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CORAL BRASILIERA DE PESQUISAS E DESENVOLVIMENTO LTDA Soc
Original Assignee
CORAL BRASILIERA DE PESQUISAS E DESENVOLVIMENTO LTDA Soc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CORAL BRASILIERA DE PESQUISAS E DESENVOLVIMENTO LTDA Soc filed Critical CORAL BRASILIERA DE PESQUISAS E DESENVOLVIMENTO LTDA Soc
Publication of EP0214265A1 publication Critical patent/EP0214265A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/37—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from fungi
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/14—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from fungi, algea or lichens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • This invention relates to antigens, their isolation from subjects suffering from the associated malady, to antibodies against the antigens, and to their respective uses in therapy and diagnosis.
  • Candida is a fungus which is pathogenic in humans who are i muno-suppressed.
  • Systemic candidosis is a well-known complaint. It is associated with dissemination of Candida species throughout the blood stream and invading deep tissues. This occurs in patients with an underlying lympho-proliferative disorder, or after surgery.
  • the diagnostic criteria are (1) cultural and histological evidence from a deep organ biopsy at necropsy or during life, and (2) positive blood cultures.
  • EP-A-0141616 and O-A- disclose monoclonal antibodies against antigens of the genus Candida. A description of the various species within the genus is given in the latter, the relevant contents of which are incorporated herein by reference.
  • a first aspect of the present invention lies in candidosis antigens, for therapeutic or diagnostic use.
  • a second aspect of the present invention lies in antibodies, more preferably human antibodies and most preferably human monoclonal antibodies, against a candidosis antigen, e.g. an antigen as defined above, for therapeutic or diagnostic use, and in such human monoclonal antibodies per se.
  • An antigen of the invention may be obtained by purification of a blood sample obtained from a subject suffering from systemic candidosis, followed by purification.
  • An antigen of the invention may be provided in suitable form for therapeutic or diagnostic use, e.g. in substantially pure form and/or as part of the kit containing one or more other reagents.
  • the antigen is preferably provided for use in the form of a vaccine, e.g. for intravenous or percutaneous administration to a human subject.
  • An antigen of the present invention may be characterised by a molecular weight o ⁇ from 45 to 55 kD, and more specifically about 47 kD.
  • An antigen of the invention may be used to raise serum in an animal, e.g. in rabbits.
  • the rabbit anti-serum may then be used to detect candidal antigens in human sera.
  • An antigen of the invention may be of general use as a diagnostic reagent, as the basis of antigen tests for systemic candidosis.
  • Antigens of the invention, refractionated if necessary, may be used in the invention .described in O-A-8600927.
  • Antibodies of the invention may be provided for use in the form of a pharmaceutical composition. They may be used in the treatment of systemic candidosis. They may be given directly or coupled to certain drugs, e.g. anti-candidosis drugs such as amphotericin B or 5-fluorocytosine.
  • This Example illustrates how an antigen of the invention may be obtained from yeast.
  • Yeasts (Candida albicans species) were grown overnight in Sabouraud's agar or in a defined minimal accommodation supplemented with amino-acids. They were harvested in distilled water, and crushed using a press; a "pressate” was prepared by fragmentation in an "X press” (LKB, Bromnia, Sweden ⁇ at a pressure of 200 mPa. Any suitable form of mechanical destruction may be used instead of a press, e.g. glass balls may be used.
  • the pressate was frozen at -70 C overnight and then loaded with yeast. This product was then placed within plastic bags in a 70% methanol bath containing cardice, for 30 minutes. The plastic bags prevented methanol from penetrating into the pressate containing the yeast. The pressate was taken from the bath, the plastic bags were removed, and a pressure of 200 mPa was exerted.
  • This Example illustrates the preparation of an antigen from human serum.
  • Serum was obtained from patients with systemic candidosis, and desalted. This desalted serum was used as an antigen preparation in an immunoblotting system.
  • the nitrocellulose was then incubated at 25 C for 2 hours with the anti-serum raised against the yeast "pressate", diluted 1:50 in 3% BSA - 0.05% Tween 20 in buffered saline. After washing five times over 30 minutes in 0.9% saline - 0.05% Tween 20, it was incubated for 1 hour at 25 C with alkaline phosphatase-conjugated goat anti-rabbit IgG. The conjugate was diluted 1:1000, immediately before use in 3% BSA in buffered saline. After washing, the nitrocellulose was incubated for 15 minutes at 25 C in a freshly prepared and filtered mixture of equal volumes of naphthol ASMX phosphate and Fast Red TR salt.
  • This Example illustrates the further purification of an antigen obtained, as in Example 2, from human serum.
  • Serum was obtained from a patient with candidosis, and was shown, by enzyme immunoassay against antigen prepared as in Examples 1 and 2, to contain antibody against antigens of Candida albicans, including the antigen of 45 to 47 kD described above.
  • Immunoglobulin G (IgG) from the serum was purified by adsorption on to protein A (which has a specific affinity for IgG) and then elution. This yielded 110 mg IgG which was shown, by polyacrylamide gel electrophoresis, to be pure.
  • the IgG was coupled to 20 ml Sepharose CL 6B using cyanogen bromide (a standard method) .
  • the IgG-Sepharose complex was packed into a column and washed, firstly with 3 column volumes of glycine-HCl buffer, pH 2.8, and secondly with 5 column volumes of PBS.
  • the column was then washed through with glycine-HCl buffer, pH 2.8, to elute the Candida antigen specifically bound to the IgG-Sepharose.
  • the eluate was collected in
  • the column was then washed again with PBS in readiness for the next sample of desalted serum.
  • a sodium dodecyl polyacrylamide gel was prepared by:
  • Transblot cell A current of 350 mA was applied for 1.5 hours, so that antigen was transferred from the gel to the paper. The paper was then removed, and soaked in
  • 35 paper was then washed five times in normal saline with 0.05% Tween 20, and then incubated at 25 C for 1 hour with a goat antibody against rabbit or human (as appropriate) immunoglobulin conjugated with alkaline phosphatase, diluted 1:1000 in BSA-TRIS.
  • the paper was washed as before, and then incubated for 15 min at 25 C in a freshly prepared and filtered mixture of equal volumes of naphthol ASMX phosphate and Fast Red TR salt.
  • the paper was then washed again as before, and dried in air, when characteristic bands of stained immune complexes were visible on the paper.
  • monoclonal antibody may be used, prepared by the procedure described in either WO-A-8600927 or O-A-8600928 , the contents of which are incorporated herein by reference.
  • the antibody may be diluted 1:7 in the buffered BSA.
  • the antigenic supernatant obtained by the procedure of Example 1 is used to raise hyperimmune serum in New ' Zealand white rabbits.
  • the rabbit anti-serum is then used to detect candidal antigens in human sera as described in Example 4.
  • the rabbits are immunised either by direct intravenous injection or else by combining antigen with Full Freund's adjuvant and immunising subcutaneously.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Mycology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

Un antigène purifié de candidose ayant un poids moléculaire compris entre 45 et 55 kD peut être obtenu et utilisé dans un vaccin. Des anticorps, par exemple un anticorps monoclonal humain, peuvent être obtenus et utilisés en thérapie, par exemple avec un agent fongicide.A purified candidiasis antigen having a molecular weight between 45 and 55 kD can be obtained and used in a vaccine. Antibodies, for example a human monoclonal antibody, can be obtained and used in therapy, for example with a fungicidal agent.

Description

AXON
-1-
ANTIGENS, ANTIBODIES AND THEIR USES FIELD OF THE INVENTION
This invention relates to antigens, their isolation from subjects suffering from the associated malady, to antibodies against the antigens, and to their respective uses in therapy and diagnosis. BACKGROUND OF THE INVENTION
Candida is a fungus which is pathogenic in humans who are i muno-suppressed. Systemic candidosis is a well-known complaint. It is associated with dissemination of Candida species throughout the blood stream and invading deep tissues. This occurs in patients with an underlying lympho-proliferative disorder, or after surgery. The diagnostic criteria are (1) cultural and histological evidence from a deep organ biopsy at necropsy or during life, and (2) positive blood cultures.
EP-A-0141616 and O-A- (PCT/GB85/00476) disclose monoclonal antibodies against antigens of the genus Candida. A description of the various species within the genus is given in the latter, the relevant contents of which are incorporated herein by reference. SUMMARY OF THE INVENTION
A first aspect of the present invention lies in candidosis antigens, for therapeutic or diagnostic use. A second aspect of the present invention lies in antibodies, more preferably human antibodies and most preferably human monoclonal antibodies, against a candidosis antigen, e.g. an antigen as defined above, for therapeutic or diagnostic use, and in such human monoclonal antibodies per se. DETAILED DESCRIPTION OF THE INVENTION
An antigen of the invention may be obtained by purification of a blood sample obtained from a subject suffering from systemic candidosis, followed by purification. An antigen of the invention may be provided in suitable form for therapeutic or diagnostic use, e.g. in substantially pure form and/or as part of the kit containing one or more other reagents. The antigen is preferably provided for use in the form of a vaccine, e.g. for intravenous or percutaneous administration to a human subject. An antigen of the present invention may be characterised by a molecular weight o± from 45 to 55 kD, and more specifically about 47 kD. An antigen of the invention may be used to raise serum in an animal, e.g. in rabbits. The rabbit anti-serum may then be used to detect candidal antigens in human sera. An antigen of the invention may be of general use as a diagnostic reagent, as the basis of antigen tests for systemic candidosis. Antigens of the invention, refractionated if necessary, may be used in the invention .described in O-A-8600927.
Antibodies of the invention may be provided for use in the form of a pharmaceutical composition. They may be used in the treatment of systemic candidosis. They may be given directly or coupled to certain drugs, e.g. anti-candidosis drugs such as amphotericin B or 5-fluorocytosine.
The following Examples 1, 2, 3 and 5 illustrate the invention. The following abbreviations are used: PBS = phosphate-buffered saline; BSA = bovine serum albumin; BSA-TRIS = 3% BSA in TRIS-buffered saline, pH 7.4. Percentages are by weight, or by volume with respect to liquids. ("Millipore" , "Millex" , "Sepharose" and "Tween" may be registered Trade Marks) . Example 1
This Example illustrates how an antigen of the invention may be obtained from yeast.
Yeasts (Candida albicans species) were grown overnight in Sabouraud's agar or in a defined minimal mediu supplemented with amino-acids. They were harvested in distilled water, and crushed using a press; a "pressate" was prepared by fragmentation in an "X press" (LKB, Bromnia, Sweden^ at a pressure of 200 mPa. Any suitable form of mechanical destruction may be used instead of a press, e.g. glass balls may be used.
The pressate was frozen at -70 C overnight and then loaded with yeast. This product was then placed within plastic bags in a 70% methanol bath containing cardice, for 30 minutes. The plastic bags prevented methanol from penetrating into the pressate containing the yeast. The pressate was taken from the bath, the plastic bags were removed, and a pressure of 200 mPa was exerted.
The process was repeated three times, to obtain 90% or more disruption of cells. The distintegrated cells were removed from the press and centrifuged at 38,000 g for 1.5 hours at 4 C. The supernatant was filtered through a 0.22 μm Millipore-membrane (Millex) , to ensure sterility. Example 2
This Example illustrates the preparation of an antigen from human serum.
Serum was obtained from patients with systemic candidosis, and desalted. This desalted serum was used as an antigen preparation in an immunoblotting system.
It was run on a SDS Polyacrylamide electrophoresis gel to separate it from the other components of serum. A Transblotting set was used to transfer it from the gel to nitrocellulose paper. It was detected by a modified enzyme-linked immunosorbent assay, using a rabbit anti-serum raised against a yeast "pressate" (see above) . Transfer was performed at room temperature, using a current of 350 mA for 1.5 hours, in a Bio-Rad Trans-Blot cell. Free protein sites were saturated by incubation in 3% BSA in buffered saline (0.9% NaCl - 10 mM TRIS, pH 7.4) at 4 C overnight.
The nitrocellulose was then incubated at 25 C for 2 hours with the anti-serum raised against the yeast "pressate", diluted 1:50 in 3% BSA - 0.05% Tween 20 in buffered saline. After washing five times over 30 minutes in 0.9% saline - 0.05% Tween 20, it was incubated for 1 hour at 25 C with alkaline phosphatase-conjugated goat anti-rabbit IgG. The conjugate was diluted 1:1000, immediately before use in 3% BSA in buffered saline. After washing, the nitrocellulose was incubated for 15 minutes at 25 C in a freshly prepared and filtered mixture of equal volumes of naphthol ASMX phosphate and Fast Red TR salt. Example 3
This Example illustrates the further purification of an antigen obtained, as in Example 2, from human serum. Serum was obtained from a patient with candidosis, and was shown, by enzyme immunoassay against antigen prepared as in Examples 1 and 2, to contain antibody against antigens of Candida albicans, including the antigen of 45 to 47 kD described above. Immunoglobulin G (IgG) from the serum was purified by adsorption on to protein A (which has a specific affinity for IgG) and then elution. This yielded 110 mg IgG which was shown, by polyacrylamide gel electrophoresis, to be pure.
The IgG was coupled to 20 ml Sepharose CL 6B using cyanogen bromide (a standard method) . The IgG-Sepharose complex was packed into a column and washed, firstly with 3 column volumes of glycine-HCl buffer, pH 2.8, and secondly with 5 column volumes of PBS.
2-3 ml desalted serum (as from Example 2) were passed through the column at a rate of 0.5 l/min, and the column was then washed with PBS until the optical densi'ty of the filtrate, measured at 280 nm, was zero.
The column was then washed through with glycine-HCl buffer, pH 2.8, to elute the Candida antigen specifically bound to the IgG-Sepharose. The eluate was collected in
5 vessels containing solid TRIS , to raise the pH to 8.0.
The column was then washed again with PBS in readiness for the next sample of desalted serum.
Each sample of eluted antigen was placed in a dialysis sac, and covered with solid sucrose to
10 concentrate the antigen. The antigen was then dialysed against distilled water.
Example 4
This Example illustrates an assay for antigen obtained by any of the methods described in Examples 1, 2
15 and 3.
A sodium dodecyl polyacrylamide gel was prepared by
. a standard method. Aliquots of the antigen (0.025 ml) in distilled water were applied into sample slots of the gel, and a current of 50 mA at 150 volts -was applied
20 across the gel for 6 hours. During this time, the components of the sample migrated in the gel at a rate roughly proportional to their molecular size.
The current was switched off. The gel was removed from its glass supporting plates and mounted, together
25 with a sheet of nitrocellulose paper, in a Bio-Rad
Transblot cell. A current of 350 mA was applied for 1.5 hours, so that antigen was transferred from the gel to the paper. The paper was then removed, and soaked in
BSA-TRIS at 4 C overnight, to saturate free binding sites
30 on the paper. _% • The nitrocellulose paper was then incubated with anti-serum prepared as in Example 3 (or from patients with, or convalescing from, candidosis) diluted 1:50 in
BSA-TRIS with 0.05% Tween 20 for 2 hours at 25 C. The
35 paper was then washed five times in normal saline with 0.05% Tween 20, and then incubated at 25 C for 1 hour with a goat antibody against rabbit or human (as appropriate) immunoglobulin conjugated with alkaline phosphatase, diluted 1:1000 in BSA-TRIS. The paper was washed as before, and then incubated for 15 min at 25 C in a freshly prepared and filtered mixture of equal volumes of naphthol ASMX phosphate and Fast Red TR salt. The paper was then washed again as before, and dried in air, when characteristic bands of stained immune complexes were visible on the paper.
Instead of anti-serum, monoclonal antibody may be used, prepared by the procedure described in either WO-A-8600927 or O-A-8600928 , the contents of which are incorporated herein by reference. The antibody may be diluted 1:7 in the buffered BSA. Example 5
The antigenic supernatant obtained by the procedure of Example 1 is used to raise hyperimmune serum in New ' Zealand white rabbits. The rabbit anti-serum is then used to detect candidal antigens in human sera as described in Example 4. The rabbits are immunised either by direct intravenous injection or else by combining antigen with Full Freund's adjuvant and immunising subcutaneously.

Claims

1. A candidosis antigen, for therapeutic or diagnostic use.
2. An essentially pure candidosis antigen.
3. An antigen according to claim 1 or claim 2, which has a molecular weight of from 45 to 55 kD.
4. An antigen according to claim 1 or claim 2, which has a molecular weight of about 47 kD.
5. A human antibody against a candidosis antigen, for therapeutic or diagnostic use.
6. A human monoclonal antibody against a candidosis antigen.
7. A human monoclonal antibody against a candidosis antigen, for therapeutic or diagnostic use.
8. An antibody according to any of claims 5 to 7, in which the antigen is as defined in claim 3 or claim 4.
9. A vaccine which comprises an antigen according to any of claims 1 to 4.
10. A -pharmaceutical composition which comprises an antibody according to any of claims 5 to 8.
11. A composition according to claim 10, which additionally comprises an anti-candidosis drug.
12. A composition according to claim 11, in which the drug is amphotericin B or 5-fluorocytosine.
13. A method of treating a human or other animal subject prone to or suffering from candidosis, which comprises administering to the subject an anti-candidosis effective amount of an antigen according to any of claims 1 to 4, an antibody according to any of claims 5 to 8, a vaccine according to claim 9 or a composition according to any of claims 10 to 12.
EP86901937A 1985-03-12 1986-03-12 Antigens, antibodies and their uses Withdrawn EP0214265A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8506373 1985-03-12
GB858506373A GB8506373D0 (en) 1985-03-12 1985-03-12 Antigens antibodies

Publications (1)

Publication Number Publication Date
EP0214265A1 true EP0214265A1 (en) 1987-03-18

Family

ID=10575866

Family Applications (1)

Application Number Title Priority Date Filing Date
EP86901937A Withdrawn EP0214265A1 (en) 1985-03-12 1986-03-12 Antigens, antibodies and their uses

Country Status (4)

Country Link
EP (1) EP0214265A1 (en)
JP (1) JPS62502193A (en)
GB (1) GB8506373D0 (en)
WO (1) WO1986005400A1 (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8915019D0 (en) * 1989-06-30 1989-08-23 Matthews Ruth C Medicaments
GB9417880D0 (en) * 1994-09-06 1994-10-26 Auspharm Int Ltd Vaccine
GB2304347A (en) * 1995-08-11 1997-03-19 Boeringer Ingelheim Vetmedica Antigenic preparations
US6136794A (en) * 1998-02-02 2000-10-24 Merck & Co., Inc. Platelet aggregation inhibition using low molecular weight heparin in combination with a GP IIb/IIIa antagonist
WO2001073441A1 (en) * 2000-03-27 2001-10-04 Mochida Pharmaceutical Co., Ltd. Kit for detecting fungal infection of specimens in oral cavity
US20100113355A1 (en) 2007-04-27 2010-05-06 Naresh Chennamsetty Novel antibody molecules and nucleic acids binding to fungal stress protein hsp90

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU547928B2 (en) * 1981-11-03 1985-11-14 Sutka, K. Antigenic preparation from candida guilliermondii
SE8401943L (en) * 1983-04-08 1984-11-22 Kureha Chemical Ind Co Ltd ANTIBODY FOR CANDIDA FUNGI
US4670382A (en) * 1983-12-02 1987-06-02 Temple University--of the Commonwealth System of Higher Education Monoclonal antibody to Candida albicans cytoplasmic antigens and methods of preparing same
GB8426459D0 (en) * 1984-10-19 1984-11-28 Technology Licence Co Ltd Monoclonal antibodies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8605400A1 *

Also Published As

Publication number Publication date
WO1986005400A1 (en) 1986-09-25
JPS62502193A (en) 1987-08-27
GB8506373D0 (en) 1985-04-11

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