EP0479971A1 - Nouvelles proteines, nouveaux peptides, et nouvelles sequences d'adn ou d'arn correspondantes et sondes utilisees dans le diagnostic de la tuberculose - Google Patents

Nouvelles proteines, nouveaux peptides, et nouvelles sequences d'adn ou d'arn correspondantes et sondes utilisees dans le diagnostic de la tuberculose

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Publication number
EP0479971A1
EP0479971A1 EP91906940A EP91906940A EP0479971A1 EP 0479971 A1 EP0479971 A1 EP 0479971A1 EP 91906940 A EP91906940 A EP 91906940A EP 91906940 A EP91906940 A EP 91906940A EP 0479971 A1 EP0479971 A1 EP 0479971A1
Authority
EP
European Patent Office
Prior art keywords
tuberculosis
protein
human
diagnosis
kda
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Withdrawn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
EP91906940A
Other languages
German (de)
English (en)
Inventor
Jagannath Chinnaswamy
Balganesh Meenakshi
Ramasastry Srinivasa Bachally
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.)
AstraZeneca AB
Original Assignee
Astra AB
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Filing date
Publication date
Application filed by Astra AB filed Critical Astra AB
Publication of EP0479971A1 publication Critical patent/EP0479971A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1267—Gram-positive bacteria
    • C07K16/1289—Mycobacteriaceae (F)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/35—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Mycobacteriaceae (F)
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues

Definitions

  • the 17 kDa protein antigen which has an N-terminus of A T T L P V Q R (aa 1-8) has atleast three specific antibody binding epitopes located on linear peptides of sequences, R A T Y D K R Y E V R (aa 91-101) and S E F A Y G S F V R (aa 68-77) which were useful in a micro ELIS ⁇ for the early diagnosis of human tuberculosis by the detection of specific antibodies.
  • the 17 kDa protein antigen which was mitogenic for human tuberculous peripheral blood lymphocytes was found to carry three predicted T-cell epitopes on linear peptides of sequences, S E F A Y G S F V R (aa 68-77) and A E L P G V D P D C D V C I T R (aa 107-122) .
  • the 17 kDa antigen of WL_ tuberculosis (SII 1) which thus had both B and T cell reactive properties was found to contain 131 amino acids and potentially applicable in the immuno diagnosis, immuno therapy and immuno prophylaxis of human tuberculosis.
  • the present invention relates to a novel 17 kDa protein antigen of Kycobacterium tuberculosis (South Indian Isolate SII 1) and certain peptide fragments derived therefrom, and to the use of the said antigen, and of the peptide fragments
  • the invention also relates to the DNA sequence coding for the said 17 kDa antigen, to DNA sequences coding for the said peptide fragments derived from the 17 kDa antigen and to the DNA and RNA probes constructed on the basis of the protein sequence of the 17 kDa antigen including the sequences of the peptide fragments of the 17 kDa antigen.
  • a major field of use is the use of 17 kDa antigen and peptide fragments thereof in immuno diagnosis of tuberculosis.
  • a further field of use is the use of the 17 kDa antigen or of the said peptide sub structures thereof for the preparation of a vaccine against tuberculosis.
  • a further field of use is the use of the 17 kDa antigen or its sub structure peptides for the detection of T cell proliferation by skin tests or invitro tests in man. This last mentioned field of use is of importance in the possible treatment of human cancer by the boosting of cellular immunity.
  • a further field of use is the use of the 17 kDa antigen or its sub structure peptides for the laboratory production of cellular growth factors and enzymes.
  • SUBSTITUTE SHEET countries has posed a problem of secondary infection with ycobacteria including M.tuberculosis.
  • tuberculous specimen is not easy under field conditions and atlea ⁇ t 10 4 bacilli/ml are required for effective screening.
  • Many tuberculous specimens like cerebro spinal fluids from tuberculous meningitis infrequently contain bacilli.
  • bacteriological culture generally
  • SUBSTITUTESHEET takes 6 to 8 weeks and is expensive as a routine diagnostic measur .
  • tuberculin skin test lacks sensitivity and specificity and takes about 3 days for completion. Since chemotherapy of TB requires compliance for atleast 6 months, many patients who are irregular in treatment develop drug resistance and transmit live bacilli. Finally, the traditional 3CG vaccination has now been found to give varying levels of protection depending upon geographic regions.
  • Mycobacteria are powerful iamunogens * for man and aniaal ⁇ , as evidenced by their use in immuno adjuvants to boost iaaune responses.
  • many antigens derived from M.tuberculosis have been known to induce the formation of specific antibodies and proliferative lymphocytes among TB patients (Ivanyi et al., 1988) and experimental animal models.
  • the detection of an antibody response in TB has a potential application in early diagnosis.
  • the study of M.tuberculosis specific T lymphocytes has application in early diagnosis by skin tests and development of protective vaccines.
  • Table I M.tuberculosis protein antigens identified by N-terminal amino acid sequences.
  • An ELISA kit for diagnosing TB using A60 antigen present in all mycobacteria has been introduced by ANDA diagnostics (France) . The test is thus not specific for human TB alone.
  • Phenotypic variation in virulence is known among the M.tuberculosis strains isolated in South India (Naganathan et al 1987), the molecular basis for which is not yet established. Abou Zeid et al, (1988) found that a 13 kDa protein antigen was present in phage type II virulent
  • a 17 kDa protein antigen was found to be present among the isolates of M.tuberculosis.
  • the i ⁇ muno chemical features of this antigen are disclosed under this invention.
  • the 17 kDa protein antigen of M.tuberculosis (SII 1) as defined below and certain sub structures (peptides) of 17 kDa protein antigen as defined below.
  • SUBSTITUTESHEET 6 The use of the 17 kDa protein antigen or sub structures (peptides) thereof for the treatment of tuberculosis.
  • DNA or RNA probes constructed on the basis of the protein sequence of the 17 kDa antigen or sub structures (peptides) thereof for diagnosis of tuberculosis.
  • Such probes can be constructed by methods known in the art. Labelling of such probes can be done by known methods such as radioisotope incorporation or by non radio-active labelling use for example, biotin.
  • a method for diagnosis of human tuberculosis by interacting a body fluid such as serum from a patient to be diagnosed with a 17 kDa protein as defined in paragraph 5 above.
  • a method for in vitro detection of human tuberculosis which comprises contacting a sample of a body fluid such as sputum, CSF, pleural fluid or serum from a patient with a monoclonal antibody as defined in paragraph 10 in labelled form.
  • a method for in vitro detection of human tuberculosis which comprises contacting a sample of a body fluid such as sputum, CSF, pleural fluid or serum from a patient with a monoclonal antibody as defined in paragraph 10 in labelled form.
  • a method for in vitro detection of human tuberculosis which comprises contacting a sample of a body fluid such as sputum, CSF, pleural fluid or serum from a patient with a polyclonal antibody as defined in paragraph 3 in labelled form.
  • a micro organism expressing a 17 kDa protein or sub structures thereof as disclosed in paragraph 1 above.
  • a vaccine against tuberculosis developed on the basis of the 17 kDa antigen or sub structure peptides thereof as disclosed in paragraph 1 above.
  • Such a vaccine can be a product of genetically engineered organisms such as Salmonella, Vaccinia virus etc.
  • the present invention is exemplified by but not limited to the diagnosis, therapy or prophylaxis of diseases, especially diagnosis of M.tuberculosis infection.
  • Epidemiological screening, forensic investigations, determination of food contaminations, public health surveys, preventive medicine, veterinary and agricultural applications with regard to the diagnosis of infectious agents may be covered by this disclosure.
  • Fig. 1 shows the HPLC profile of 17 kDa antigen.
  • Tryptic map 30 ug of 17 kDa protein was digested with TPCK treated trypsin with an enzyme to substrate ratio of 1:50 in o 0.1 M ammonium bicarbonate buffer, pH 7.8 at 37 C for 5 h.
  • the tryptic digest was fractionated by HPLC on RP 18 column (0.46 x 25 cm) equilibrated with solvent A (0.1% TFA in water) and the peptides were eluted with a gradient of solvent B (70% acetonitrile containing 0.085% TFA) from 0 to 65% in 60 ain.
  • solvent B 70% acetonitrile containing 0.085% TFA
  • V8 protease aap 30 ug of 17 kDa antigen was treated with o staphylococcal V8 protease for 48 h in 0.07% ammonia at 37
  • the molar ratio of the enzyme to substrate was 1:25.
  • the various peptides in the enzyme digest were purified on an
  • the peptide profile is shown in Fig. 3.
  • the amino acid sequence analysis of the protein and the peptide was done using protein sequencer model 77A (Applied Biosy ⁇ tems Inc., USA) with an on line PTH amino acid analyser.
  • the sample was solubilized in 10% formic acid and fixed onto a polybrene coated (1 g) TFA treated glass fibre disc and used for sequencing.
  • the first 18 amino acids from the N-terminal was determined using the whole protein. Based on the amino acid sequences of the tryptic peptides, V8 protease was selected to generate the peptides that could give the overlaps for the tryptic peptides. The alignment of both tryptic and V8 protease peptides gave the complete sequence for the 17 kDa antigen. The details of the overlaps are given in Fig. 4.
  • the protein has A9, C3, Dll, E10, F9, G8, H2, 17, K4, Lll, M2, P9, Q2, R12, 88, T9, Vll and Y4. It is significant in not having tryptophan and a ⁇ paragine.
  • the protein is acidic in nature since it has 5 acidic aain acids (D+E-21) in excess of the total number of basic aaino acids (R+K-16) .
  • the protein has 131 aaino acids that account for a molecular weight of 14,762.
  • M. tuberculosis (SII 1) , M. tuberculosis ATCC 27294, H.phlei, M ⁇
  • FICA Freund's incomplete adjuvant
  • this experiment confirms that a polyclonal or monoclonal antibody can be produced in the mouse which recognize the protein structure of 17 kDa antigen or sub structures (peptides) thereof.
  • Such antibodies in particular the monoclonal antibodies can be used in an antigen detection method like the sandwich ELISA for the detection of the 17 kDa antigen or sub structures thereof among human tuberculosis specimen leading to immuno diagnosis of tuberculosis.
  • Sera derived from 24 healthy persons and 20 culture proven TB patients were titrated against the 17 kDa antigen as follows.
  • PVC Dynatech plates were coated with 1 ug/ l PBS of electro o eluted 17 kDa antigen for 24 h at 22 C.
  • PBS-BSA blocked plates were then titrated against duplicate (1/200) dilutions o of sera which were incubated at 22 C for 2.5 h. Washed plates received anti human IgG HRP conjugate for 1.5 h.
  • Washed plates were then assayed with O-phenylene diamine substrate and read at 492 na.
  • Table II shows that the 17 kDa antigen had a sensitivity of 70% and specificity of 85%
  • Sensitivity Known positivity among TB patients
  • Specificity Known negativity among healthy controls
  • ELISA + OD 492 n >-0.3 at 1/200 dilation (-mean + 2SD of OD 492 na for healthy controls, n-24].
  • M.tuberculosis strains can be used in a micro ELISA system for the immuno diagnosis of tuberculosis in man.
  • the peptides YEVR and ATYDK were mutually inhibitive thus indicating that they were a part of a complete antibody epitope, which was confirmed also by the determination of the complete structure of the 17 kDa antigen as in section 5.2.2, Fig 4.
  • the other four _peptides were linear and probably conformational in the presentation of the antibody epitope.
  • the peptides of the following aaino acid sequences were synthesized by solid phase aethod of
  • RATYDKRYEVR Sensitivity 65%; Specificity 95%
  • SEFAYGSFVR Sensitivity 66%; Specificity 95*
  • the antibody epitope mapping as described has thus indicated that defined sub structures or peptides of 17 kDa antigen can be synthesized and used for the immunodiagnosis of human tuberculosis in micro ELISA.
  • the peptide of the sequence RATYDKRYEVRDFDGRAEL was synthesized and found to have a sensitivity of 86.6% and a specificity of 100% when tested on CSF samples from culturtproven TBM patients and controls. This peptide is accordingly particularly suitable for use in place of the 17 kDa antigen in the ELISA test. 5.3.5 Demonstration that 17 kDa antigen is lympho proliterative
  • PBL Peripheral blood lymphocytes
  • T cell stimulatory epitopes were located on peptides of the following sequences: SEFAYGSFVR AELPGVDPDCDVCITK
  • the 17 kDa antigen or sub structures can te used to stimulate human peripheral blood lymphocytes. Since stimulated lymphocytes elaborate several cellular growth and differentiation factors which contribute to the vaccine effect of 17 kDa antigen or its sub structures, the 17 kDa antigen can be used at the first instance as a vaccine against TB and also for non- specifically boosting cellular immunity.
  • Figure 6 shows the primary structure of the 17 kDa antigen from M.tuberculosis containing the biologically active regions, although similar activity need not be ruled out in the unmarked regions.
  • the present invention describes the immunoche ical properties of a novel 17 kDa protein antigen from M.tuberculosis (SII 1 strain) .
  • M.tuberculosis causes tuberculosis worldwide aaong 16 million people. Because of inadequacy of the diagnostic procedures available now the disease has not yet been eradicated.
  • the focus of research in recent years has been the development of immuno diagnostic methods for detecting TB at an early stage as well identification of suitable candidates for vaccination since the traditional BCG vaccine has given only a partial protection against TB.
  • SUBSTITUTE SHEET SEFAYGSFVR which carried antibody binding epitopes for diagnosis of TB. Further, it contained two peptides which carried predicted T cell stimulating regions in sequences, SEFAYGSFVR and AELPGVDPDCDVCITR. The latter two peptides presumably contributed to the T cell stimulating property of the whole 17 kDa antigen described in this invention. The T cell stimulating property of the 17 kDa antigen and its sub structure peptides means that they could be used in therapy and vaccination for TB. 7. Figure legends.
  • Fig. 1 HPLC analysis of the electro eluted 17 kDa protein antigen from M. tuberculosis (SII 1).
  • HPLC conditions RP 18 column (LKB, 10 um pore size), A: 0.1% TFA in water, B: 0.085% TFA in 70% aceto nitrile, Gradient: 0 to 65% B in 40 min. Sensitivity: 0.08,220 nm.
  • Fig. 2 Tryptic peptides of 17 kDa protein antigen from
  • SII 1 M.tuberculosis (SII 1) fractionated by HPLC on RP 18 (LKB,10 um pore size).
  • Amino acid sequence Sequence determined are drawn against each peptide.
  • FIG. 3 V8 protease peptides of 17 kDa protein antigen from M.tuberculosis (SII 1) fractionated by HPLC on RP 18 (LKB, pore size 10 um) .
  • Trp M.tuberculosis (SII 1) showing the alignment of peptides. Trp:
  • SUBSTITUTE SHEET arrows denote the amino acid sequence obtained with the whole protein.
  • AA 68 to 77 Antibody and T cell epitopes present.
  • AA 91 to 101 Antibody epitope present.
  • AA 107 to 122 Two T cell epitopes present.

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

Abstract

On décrit les propriétés immunochimiques d'un antigène protéique de 17 kDa, fractionné, purifié et séquencé pour les acides aminés de Mycobacterium tuberculosis (isolat sud-indien, SII 1), qui est la cause de la tuberculose chez l'homme, auprès de 16 millions de patients dans le monde entier. L'antigène protéique de 17 kDa, qui comporte une N-terminaison de A T T L P V Q R (aa 1-8) possède au moins trois épitopes spécifiques de liaison d'anticorps situés sur des peptides linéaires des séquences R A T Y D K R Y E V R (aa 91-101) et S E F A Y G S F V R (aa 68-77), qui se sont avérés utiles dans un micro-ELISA pour le diagnostic précoce de la tuberculose chez l'homme par détection d'anticorps spécifiques. On a constaté que l'antigène protéinique de 17kDa, qui s'est révélé mitogène pour les lymphocytes sanguins périphériques, portait trois épitopes prédits de lymphocytes T sur des peptides linéaires des séquences S E F A Y G S F V R (aa 68-77) et A E L P G V D P D C D V C I T R (aa 107-122). On a constaté que l'antigène de 17 kDa de M. tuberculosis (SII 1), qui possédait donc des propriétés de réaction à la fois aux lymphocytes B et T, contenait 131 acides aminés et qu'il peut être appliqué dans l'immunodiagnostic, immunothérapie et immunoprophylaxie de la tuberculose chez l'homme.
EP91906940A 1990-03-27 1991-03-22 Nouvelles proteines, nouveaux peptides, et nouvelles sequences d'adn ou d'arn correspondantes et sondes utilisees dans le diagnostic de la tuberculose Withdrawn EP0479971A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9001105 1990-03-27
SE9001105A SE9001105D0 (sv) 1990-03-27 1990-03-27 New methods foer diagnosis of tuberculosis

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EP0479971A1 true EP0479971A1 (fr) 1992-04-15

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EP (1) EP0479971A1 (fr)
CN (1) CN1060310A (fr)
AU (1) AU7564491A (fr)
BR (1) BR9105237A (fr)
IL (1) IL97572A0 (fr)
JO (1) JO1671B1 (fr)
PT (1) PT97150A (fr)
SE (1) SE9001105D0 (fr)
WO (1) WO1991014448A1 (fr)
ZA (1) ZA911855B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103063836A (zh) * 2011-10-18 2013-04-24 复旦大学附属华山医院 检测分枝杆菌感染的试剂、方法和试剂盒
CN111518165A (zh) * 2020-05-08 2020-08-11 宁夏大学 一种特异性结合结核分枝杆菌的多肽、其编码基因及应用
CN112125954A (zh) * 2020-09-28 2020-12-25 宁夏大学 特异结合卡介苗bcg的七肽、编码基因、制备方法及用途

Families Citing this family (10)

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US6752993B1 (en) 1993-11-23 2004-06-22 The Regents Of The University Of California Abundant extracellular product vaccines and methods for their production and use
JPH09505588A (ja) 1993-11-23 1997-06-03 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 多くの細胞外生成物及びそれらの製造法並びに使用
US7300660B2 (en) 1993-11-23 2007-11-27 The Regents Of The University Of California Abundant extracellular products and methods for their production and use
US6290969B1 (en) 1995-09-01 2001-09-18 Corixa Corporation Compounds and methods for immunotherapy and diagnosis of tuberculosis
US6592877B1 (en) 1995-09-01 2003-07-15 Corixa Corporation Compounds and methods for immunotherapy and diagnosis of tuberculosis
US6338852B1 (en) 1995-09-01 2002-01-15 Corixa Corporation Compounds and methods for diagnosis of tuberculosis
US6458366B1 (en) 1995-09-01 2002-10-01 Corixa Corporation Compounds and methods for diagnosis of tuberculosis
US6013660A (en) * 1996-10-02 2000-01-11 The Regents Of The University Of California Externally targeted prophylactic and chemotherapeutic method and agents
RU2130615C1 (ru) * 1998-05-18 1999-05-20 Гизатулина Надия Мансуровна Способ экспресс-диагностики туберкулеза на основе реакции латекс-агглютинации
US6465633B1 (en) 1998-12-24 2002-10-15 Corixa Corporation Compositions and methods of their use in the treatment, prevention and diagnosis of tuberculosis

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EP0345299A1 (fr) * 1987-02-02 1989-12-13 Whitehead Institute For Biomedical Research GENES DE $i(MYCOBACTERIUM TUBERCULOSIS) CODANT DES ANTIGENES DE PROTEINE
US4952395A (en) * 1987-02-26 1990-08-28 Scripps Clinic And Research Foundation Mycobacterial recombinants and peptides

Non-Patent Citations (1)

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Title
See references of WO9114448A1 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103063836A (zh) * 2011-10-18 2013-04-24 复旦大学附属华山医院 检测分枝杆菌感染的试剂、方法和试剂盒
CN103063836B (zh) * 2011-10-18 2016-03-30 复旦大学附属华山医院 检测分枝杆菌感染的试剂、方法和试剂盒
CN111518165A (zh) * 2020-05-08 2020-08-11 宁夏大学 一种特异性结合结核分枝杆菌的多肽、其编码基因及应用
CN111518165B (zh) * 2020-05-08 2021-10-01 宁夏大学 一种特异性结合结核分枝杆菌的多肽、其编码基因及应用
CN112125954A (zh) * 2020-09-28 2020-12-25 宁夏大学 特异结合卡介苗bcg的七肽、编码基因、制备方法及用途
CN112125954B (zh) * 2020-09-28 2023-02-28 宁夏医科大学总医院 特异结合卡介苗bcg的七肽、编码基因、制备方法及用途

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ZA911855B (en) 1991-12-24
SE9001105D0 (sv) 1990-03-27
CN1060310A (zh) 1992-04-15
PT97150A (pt) 1991-12-31
WO1991014448A1 (fr) 1991-10-03
AU7564491A (en) 1991-10-21
IL97572A0 (en) 1992-06-21
BR9105237A (pt) 1992-07-21
JO1671B1 (en) 1992-08-09

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