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WO1993014118A1 - Fragments de peptides de hsp71 de mycobacteria tuberculosis et leur utilisation dans le diagnostic de la tuberculose - Google Patents

Fragments de peptides de hsp71 de mycobacteria tuberculosis et leur utilisation dans le diagnostic de la tuberculose Download PDF

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Publication number
WO1993014118A1
WO1993014118A1 PCT/GB1993/000087 GB9300087W WO9314118A1 WO 1993014118 A1 WO1993014118 A1 WO 1993014118A1 GB 9300087 W GB9300087 W GB 9300087W WO 9314118 A1 WO9314118 A1 WO 9314118A1
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Prior art keywords
tuberculosis
peptide according
hsp70
sequence
patients
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PCT/GB1993/000087
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English (en)
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Juraj Ivanyi
Ashraf Elsaghier
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Medical Research Council
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    • 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)

Definitions

  • the present invention relates to peptides which are useful in diagnosing paucibacillary mycobacterial infections.
  • the paucibacillary stage of tuberculosis is very hard to detect or diagnose due to the effective absence of clinical signs and symptoms and the lack of detectable pathogen-originating antigens. Diagnosis in the multibacillary stage is relatively easy, for instance using well known smear test. Diagnosis at the paucibacillary (or smear-negative) stage is important in order that appropriate treatment and containment measures can be implemented to avoid transmission to persons at the greatest risk infection. To date efforts to improve the diagnosis of paucibacillary TB have been unsuccessful.
  • the present inventors have now identified certain peptides which may be used in detecting paucibacillary TB and other mycobacterial diseases.
  • the peptides are related to the carboxy terminal of the stress protein Hsp71 of Mycobacterium tuberculosis and corresponding heat shock proteins of other mycobacterial pathogens.
  • the present inventors consider that the carboxy terminal regions of Hsp71 and corresponding mycobacterial heat shock proteins contain species-specific determinants having linear epitopes. These linear epitopes generate an antibody response during the paucibacillary stage of infection and peptides having corresponding sequences can be used to detect the antibodies in the serum or other body fluids of the patient.
  • Peptides of the invention may be used for detecting or diagnosing a variety of paucibacillary mycobacterial diseases especially, but not limited to, tuberculosis of humans and wild or domestic mammals such as cattle, donkeys, deer and badgers.
  • the peptides may also be used in detecting or diagnosing multibacillary mycobacterial infections.
  • the present invention therefore provides a peptide comprising a sequence the same as or immunologically equivalent to a linear epitope of the carboxy terminal region of M. tuberculosis Hsp71 or a corresponding heat shock protein of any other mycobacterial pathogen.
  • the peptide comprises a sequence the same as or immunologically equivalent to a linear epitope of the carboxy terminal of M. tuberculosis Hsp71.
  • the invention will be illustrated with reference to the figures of the accompanying drawings in which:- Figure l shows the aligned carboxy terminal region sequences of M. tuberculosis Hsp71 and corresponding heat shock proteins using the internationally-accepted 1-letter code for amino acid residues.
  • Hu Human hsp70-l
  • Ec Escherichia coli dnaK
  • Lp Mvcobacterium leprae Hsp71
  • - gaps.
  • FIG. 2 shows an analysis of antigens by SDS PAGE and Western blots.
  • b Western blots developed with tuberculosis patient's serum.
  • Figure 3 gives individual serum antibody titers to mycobacterial hsp70 (M-hsp70) and human hsp70(H-hsp70 in groups of patients and controls.
  • Groups active TB(A); "self-healed” inactive TB(B); past treated inactive TB (C) ; lung fibrosis (D) ; diseases other than tuberculosis (E) ; healthy BCG-vaccinated individuals (F) (see also table 1) .
  • Group means are indicated by the horizontal bars. Boxed symbols in group B: Patients given chemoprophylaxis due to severity of chest X-ray and clinical evaluation.
  • Figure 5 gives the ratios between anti-mycobacterial and anti-human hsp70 antibody levels. Groups of patients:see legend to table 1.
  • Figure 6 Shows antibody binding to octamer peptides derived from the carboxy-terminal sequence of the hsp7i protein M.tuberculosis. Serum from a patient with sputum smear-negative pulmonary tuberculosis, diluted 1:400 was reacted with solid-phase bound peptides using the ELISA method.
  • Figure 7 Shows localization of epitopes within the carboxy-terminal hsp71 sequence. Mean absorbance values from eight adjacent octamer peptides each containing the individual amino acid residues listed on the horizontal scale. Sera tested at 1:400 dilution were collected from patients with smear-negative pulmonary tuberculosis (PT, see binding to individual peptides in figure 6) , lung disease caused by M.avium(AM) and lepromatous leprosy (LL) .
  • PT smear-negative pulmonary tuberculosis
  • A-D localisation of epitope core hexamers.
  • Figure 8 Shows semi-quantitive evalution of antibodies to four (A-D) epitopes.
  • Sera diluted 1:400 were collected from patients with smear- positive (full circle) or smear-negative
  • tuberculosis and from non- tuberculosis controls (open circles) represented by one serum each from lepromatous leprosy, lung mycobacteriosis, Crohn's disease and a healthy subject. All sera were pre ⁇ selected to contain high antibody levels to the whole hsp71 antigen. Absorbances (vertical scale) are mean values from adjacent peptides corresponding to each of the four epitopes (bottom horizontal scale) .
  • the sequences of the carboxy terminal regions of M. tuberculosis Hsp71 and the corresponding human Hsp70 and Escherichia coli dnaK molecules and the Hsp71 of ______ leprae are set out in Figure 1.
  • Four linear epitopes within the Hsp71 of M. tuberculosis are indicated by the core sequences A to D underlined in Figure 1. It is presently preferred that the peptide of the invention comprises at least one of these linear epitope core sequences or an immunological equivalent thereof.
  • Core sequences A and C, especially the latter, which appear to be more highly specific to M. tuberculosis. are preferred for selective diagnosis of paucibacillary TB in humans.
  • Core sequences B and D appear to be more immunogenic than sequences A and C but have some cross reaction between M. tuberculosis and M. leprae; these core sequences are therefore preferred for more highly sensitive diagnosis of paucibacillary TB where infection by M. leprae can be ruled out on other grounds.
  • linear epitopes may be longer or shorter than the 6-residue core sequences given in Figure 1 but are unlikely to be less than five residues in length. Accordingly, preferred peptides of the invention comprise at least any five and preferably all six amino acid residues of one of the core sequences indicated in Figure
  • More preferred peptides are octamers containing five or preferably all six of the amino acid residues of one of the core sequences and especially preferred peptides are octamers having the whole core sequence and two other residues corresponding to the two flanking residues at either the N- or C- flanks or one residue at each flank in the M. tuberculosis Hsp71 sequence given in Figure 1.
  • Other preferred peptides of the invention contain a sequence immunologically equivalent to one of the aforementioned linear epitopes, i.e. peptides which cross- react with antibodies detected by peptides containing a linear epitope sequence; more preferably such immunological equivalents contain sequences which cross-react with one. of the aforementioned core sequences.
  • the peptides of the invention may also contain sequences unrelated to Hsp7l or corresponding molecules, at either or both flanks of the core sequence or linear epitope sequence.
  • the peptide comprises a branched polylysine bearing multiple copies of a linear epitope sequence or immunological equivalent thereof.
  • Peptides of the present invention may be produced by well known peptide synthetic techniques using solid or liquid-phase reactions to assemble the peptide one amino acid residue at a time or by covalently binding preformed sub-sequences, e.g. by linking linear epitope sequences or immunological equivalents thereof to a branched polylysine or other branched structure.
  • Branched polylysines and other suitable branched structures are commercially available or described in the literature and linking of peptides to these may be achieved by conventional techniques. Techniques for identifying linear epitopes and immunological equivalents thereof are readily available to those skilled in the art.
  • the peptides of the invention may be used in any conventional immunodiagnostic test technique for detecting antibodies in a body fluid such as blood or serum.
  • the invention further provides a diagnostic test process comprising contacting a peptide as hereinbefore defined with a body fluid sample taken from an individual suspected of having a mycobacterial infection.
  • the peptide may be contacted in the liquid phase or the solid phase, in which case the peptide will be bound to a solid carrier such as the test vessel, for instance a microtitre plate, or latex beads. Binding of antibody from the sample to the peptide may be detected by any conventional technique.
  • the peptide For use in certain diagnostic procedures it may be advantageous to bind the peptide to a detectable label such as an enzyme label, a chromophore, a fluorophore or a radio-isotope or to a solid support. Binding of the peptide to a label or solid supports may be effected by conventional techniques. Peptides bound to such labels and solid supports form a further aspect of the invention. Although it is presently envisaged that the peptides of the invention will be used in in vitro diagnost i c procedures, it is possible that in. vivo techniques will be used. Accordingly, the invention further provides a peptide as hereinbefore defined, optionally bound to a label or solid support, for use in a diagnostic process practised on the human or animal body.
  • a detectable label such as an enzyme label, a chromophore, a fluorophore or a radio-isotope or to a solid support.
  • the invention further provides a process for producing a peptide as hereinbefore defined; a process for linking a peptide as hereinbefore defined to a detectable label or solid support; and tests kits containing the peptide optionally bearing a label or linked to a solid support and optionally also comprising buffer, positive or negative control materials, labelling reagents, reagents for detecting a label and other conventional components.
  • the invention will now be illustrated by the following Examples:-
  • tuberculin PPD tuberculin PPD
  • active tuberculosis 1,2,3
  • antigenic epitopes with both species-specificity and strong immunogenicity would be required.
  • mycobacterial antigens In smear-positive (multibacillary) tuberculosis (TB) , this requirement is best met by the 38 kDa protein antigen (reviewed in 4) .
  • This protein originally identified by monoclonal antibodies (10) has been sequenced by cloning its gene from the DNA of M. leprae and M tuberculosis (11,12). It belongs to the family of heat shock proteins with broadly conserved structure between prokaryotes and eukaryotes. At this is a strong structural basis for autoimmunization, it was of interest to compare serum antibody levels to both mycobacterial and human hsp 70 molecules in groups of patients and controls.
  • Serum samples All 198 tested sera were obtained from patients at the Northwick Park Hospital. (Informed consent was obtained from all patients and controls whose blood was sampled) . On the basis of clinical diagnosis, they were classified to groups listed in table 1. Patients with active tuberculosis (group A:90 total) were further classified in respect of pulmonary localization, sputum smear microscopy and bacteriological culture. The clinical parameters of patients with extrapulmonary disease have previously been described in greater detail (7) . Patients with "inactive tuberculosis" (36 total) were represented by patients with radiological evidence of old pulmonary tuberculosis without history of drug treatment (group B "self-healed") , and those with a history of drug treatment (group C "past-treated”) .
  • Groups without active or past TB were represented by patients with clinical and radiologically demonstrable lung fibrosis (group D) and by patients with other diseases such as pneumonia, sarcoidosis, bronchiactasis, carcinoma of the lung, viral infections, liver diseases or heart failure (group E) .
  • Healthy subjects were age matched adult BCG-vaccinated individuals (group F) .
  • hsp70 protein was prepared from the stress-inducible hsp70 gene (14) kindly provided by Dr Rick Morimoto, Northwestern University, Evanston, IL. , USA. It was subcloned in plasmid PET-3 (15) and expressed in E Coli using bacteriophage T 7 RNA polymerase system for selective high level expression (16) . Hsp70 protein was purified from the crude protein lysates (Jindal and Young, in preparation) .
  • Enzyme Linked Immunoassav ELISA
  • Polyvinyl microtitre plates (Nunc-Im uno plate MaxiSorp F96) were incubated with 50 ⁇ l of either M-h ⁇ p70 or H-hsp70 at concentration of 1 ⁇ g/ml or 2 ⁇ g/ml respectively at 4°C overnight. After washing once with phosphate-buffered saline containing 0.05% (w/v) "Tween 20" (PBST) , the wells were incubated with 200 ⁇ l of 2% dried milk (w/v) in PBST (PBSTM) at 37°C for 1 hr.
  • PBST phosphate-buffered saline containing 0.05%
  • the 71kDa protein of M tuberculosis has biochemical and functional features consistent with other members of the hsp family (13) and has been found in supernatants from short-term culture of tubercle bacilli (19) .
  • the extracellular location may enable contact of the molecule in its native conformation with B cells which is a requirement for effective stimulation of antibody formation.
  • hsp70 Despite the greatly conserved amino acid sequence composition of hsp70, it is of interest that existing monoclonal antibodies have been found restricted in binding mainly to pathogenic mycobacteria of the M. tuberculosis complex. M. leprae and M. scrofulaceum (10) . Following infection with Schistosoma mansoni, antibodies also exhibited only limited cross-reactivity in respect of species specific epitopes of hsp70 and arose early in the course of infection (20,21). However, sera from humans infected with malaria contained autoantibodies which reacted with human hsp70 (22) . Increased antibody levels to mycobacterial hsp70 have been found in sera of patients with active pulmonary tuberculosis (23, 24), but these studies did not show individual values and did not evaluate antibody levels in relation to the stage of disease.
  • the tips of the pins have been chemically derivatised to provide functional groups to which amino acids may be coupled in an appropriate form in peptide synthesis. All peptides have received N-terminal acetylation. Positive and negative control peptide sequences were synthesised on the same block as the test peptides to give an indication of the sensitivity being achieved in the ELISA assay.
  • the pins were incubated overnight at 4°C in a microtitre plate containing 175 ⁇ l/well of human serum diluted 1/400 in pre-coat buffer.
  • the pins were removed from the primary antibody preparation and washed four times 10 min each in a bath of 0.01 M PBS (pH 7.2) at room temperature with agitation.
  • the pins were placed in a microtitre plate containing 175 ⁇ l/well of peroxidase labelled goat anti-human IgG diluted 1/1000 in conjugated diluent (1% v/v sheep serum, 0.1% v/v Tween 20,0.1% w/v sodium casemate and 0.01 M PBS pH 7.2) and incubated at 20°C for 60 min with agitation.
  • conjugated diluent 1% v/v sheep serum, 0.1% v/v Tween 20,0.1% w/v sodium casemate and 0.01 M PBS pH 7.2
  • the pins were washed as above and placed in a microtitre plate containing 150 ⁇ l/well of substrate solution, 0.5 mg/ml of 2,2'-azino- di[3-ethyl-benthiazoline sulfonate] in citrate buffer pH 4.0 and 0.01% w/v hydrogen peroxide.
  • the reaction was stopped by removing the pins from the plate after 30 min and immediately the optical density was measured at 405 n in a Titertek "Multiscan MCC II" spectrophotometer.
  • each of the four identified epitopes have been alocated to six residues graded with the highest mean OD values. They are represented by sequences DAAVAE for epitope A, WRIGYF for epitope B, GEAGPG for epitope C and CVTGHW for epitope D ( Figure 1) . Alignment of these hexamers within the sequence of the hsp71 carboxy terminus from M.
  • tuberculosis (10) , with corresponding ssequences of M.leprae hsp70 (9), E.coli dnaK, (12) and of the human HSP70-1 gene (13) revealed, that the core of epitope A is overlapping in 5 out of the 6 core residues with the M.leprae sequence.
  • epitopes D, B and C shared only 2, 1 or no residue respectively with M.leprae.
  • the immunogenicity of protein antigens in terms of antibody formation is largely based on the recognition of epitopes displayed on native molecules by the immunoglobulin receptors of B cells (14) .
  • the epitopes which react with the bulk of antibodies in patients with tuberculosis are of confor ational nature (1, 15, 16) .
  • the need for direct contact with B cells by the native antigens is corroborated by the fact that both 38kDa and 19kDa antigens are lipoproteins, secreted from live mycobacteria (17) and resulting in the highest antibody titres in multibacillary disease (2,3).
  • hsp71 The pronounced immunogenicity of hsp71 during paucibacillary infection could be attributed to enhanced stress-induced synthesis during intracellular replication (19) , or to surface expression (20,21) enabling recognition by the Ig receptors of B cells or merely to earlier priming by multiple cross-reacting commensal microbial organisms and autologous hsp70.
  • the hsp71 protein is a predominantly intracellular constituent (8)
  • its presence in media from short-term mycobacterial cultures (22) indicates some form of secretion from live bacteria which could be contributory to its immunogenicity for B cells.
  • Ashbridge K.R. Pre ⁇ tidge R.K., Booth R.J. and Watson J.D. (1990) The mapping of a serodominant region of the Mycobacterium tuberculosis 19 kilodalton antigen. J. Immuno. 144:3137-3142.

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Abstract

Peptides comprenant une séquence similaire ou immunologiquement équivalente à un épitope linéaire de la région terminale carboxy de protéines de choc termique de Mycobacteria tuberculosis, telles que Hsp71, efficaces dans le diagnostic de la tuberculose paucibacillaire (TB). L'invention décrit également des procédés de diagnostic de TB utilisant lesdits peptides, ainsi que des kits d'essai comprenant lesdits peptides.
PCT/GB1993/000087 1992-01-17 1993-01-15 Fragments de peptides de hsp71 de mycobacteria tuberculosis et leur utilisation dans le diagnostic de la tuberculose WO1993014118A1 (fr)

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Cited By (24)

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US5750119A (en) * 1994-01-13 1998-05-12 Mount Sinai School Of Medicine Of The City University Of New York Immunotherapeutic stress protein-peptide complexes against cancer
US5830464A (en) * 1997-02-07 1998-11-03 Fordham University Compositions and methods for the treatment and growth inhibition of cancer using heat shock/stress protein-peptide complexes in combination with adoptive immunotherapy
US5837251A (en) * 1995-09-13 1998-11-17 Fordham University Compositions and methods using complexes of heat shock proteins and antigenic molecules for the treatment and prevention of neoplastic diseases
US5935576A (en) * 1995-09-13 1999-08-10 Fordham University Compositions and methods for the treatment and prevention of neoplastic diseases using heat shock proteins complexed with exogenous antigens
US5948646A (en) * 1997-12-11 1999-09-07 Fordham University Methods for preparation of vaccines against cancer comprising heat shock protein-peptide complexes
US5961979A (en) * 1994-03-16 1999-10-05 Mount Sinai School Of Medicine Of The City University Of New York Stress protein-peptide complexes as prophylactic and therapeutic vaccines against intracellular pathogens
US5985270A (en) * 1995-09-13 1999-11-16 Fordham University Adoptive immunotherapy using macrophages sensitized with heat shock protein-epitope complexes
US5997873A (en) * 1994-01-13 1999-12-07 Mount Sinai School Of Medicine Of The City University Of New York Method of preparation of heat shock protein 70-peptide complexes
US6013660A (en) * 1996-10-02 2000-01-11 The Regents Of The University Of California Externally targeted prophylactic and chemotherapeutic method and agents
US6017540A (en) * 1997-02-07 2000-01-25 Fordham University Prevention and treatment of primary and metastatic neoplastic diseases and infectious diseases with heat shock/stress protein-peptide complexes
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
US6761894B1 (en) 1993-11-23 2004-07-13 The Regents Of The University Of California Abundant extracellular products and methods for their production and use
EP1252517A4 (fr) * 2000-01-21 2004-10-20 Wistar Inst Molecules biocides, cibles macromoleculaires, et procedes de production et d'utilisation
US7015309B1 (en) 1999-06-23 2006-03-21 The Wistar Institute Of Anatomy And Biology Pyrrhocoricin-derived peptides, and methods of use thereof
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
US7449557B2 (en) 2000-06-02 2008-11-11 University Of Connecticut Health Center Complexes of alpha (2) macroglobulin and antigenic molecules for immunotherapy
US7666581B2 (en) 2001-08-20 2010-02-23 University Of Connecticut Health Center Methods for preparing compositions comprising heat shock proteins useful for the treatment of cancer and infectious disease
US8475785B2 (en) 2008-03-03 2013-07-02 The University Of Miami Allogeneic cancer cell-based immunotherapy
US8685384B2 (en) 1998-02-20 2014-04-01 University Of Miami Recombinant cancer cell secreting modified heat shock protein-antigenic peptide complex
US8728170B1 (en) 2006-12-28 2014-05-20 Boston Scientific Scimed, Inc. Bioerodible nano-fibrous and nano-porous conductive composites
US8968720B2 (en) 2008-03-20 2015-03-03 University Of Miami Heat shock protein GP96 vaccination and methods of using same
US10046047B2 (en) 2015-02-06 2018-08-14 Heat Biologics, Inc. Vector co-expressing vaccine and costimulatory molecules
US11548930B2 (en) 2017-04-04 2023-01-10 Heat Biologics, Inc. Intratumoral vaccination
US11666649B2 (en) 2016-10-11 2023-06-06 University Of Miami Vectors and vaccine cells for immunity against Zika virus

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