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Tuberculosis rv2386c protein, compositions and uses thereof

a technology of tuberculosis and rv2386c, applied in the field of polypeptides and polynucleotides, can solve the problems of fatigue, weight loss, fever and persistent cough, serious complications and death, and treatment is not sufficient to prevent the spread of the diseas

Inactive Publication Date: 2011-08-25
GLAXO GROUP LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is a major disease in developing countries, as well as an increasing problem in developed areas of the world.
Although an infection may be asymptomatic for a considerable period of time, the active disease is most commonly manifested as an acute inflammation of the lungs, resulting in tiredness, weight loss, fever and a persistent cough.
If untreated, serious complications and death typically result.
Tuberculosis can generally be controlled using extended antibiotic therapy, although such treatment is not sufficient to prevent the spread of the disease.
Infected individuals may be asymptomatic, but contagious, for some time.
In addition, although compliance with the treatment regimen is critical, patient behaviour is difficult to monitor.
Some patients do not complete the course of treatment, which can lead to ineffective treatment and the development of drug resistance.
Sensitivity and specificity have, however, been a problem with this test, and individuals vaccinated with BCG cannot always be easily distinguished from infected individuals (this is particularly important in light of the fact that BCG does not protect against latent infection).
However, this rule is not applicable to individuals with immunosuppression due to HIV infection, which may result in a PPD reaction below 10 mm in diameter); or in endemic countries, where people infected by non-tuberculosis mycobacteria can show a PPD reaction above 10 mm in diameter.
However, since ESAT-6 / CFP-10 are early stage antigens, assays based on ESAT-6 / CFP-10 may only perform optimally in recently infected people.

Method used

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  • Tuberculosis rv2386c protein, compositions and uses thereof
  • Tuberculosis rv2386c protein, compositions and uses thereof
  • Tuberculosis rv2386c protein, compositions and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification of Rv2386c as a Latent TB Vaccine Target

[0588]The gene Rv2386c also known as Mbtl, encodes for a protein which is involved in the biogenesis of hydroxyphenyloxazoline-containing siderophore mycobactins where it converts chorismate to salicylate, the starter unit for mycobacterin siderophore synthesis.

[0589]Rv2386c was selected based on a genome-wide analysis of Mycobacterium tuberculosis genes associated with dormancy phase maintenance and infectivity as in Murphy and Brown BMC. Infect. Dis. 2007 7:84-99. Potential dormancy phase gene targets in Mycobacterium tuberculosis were prioritised through a bioinformatics meta-analysis of published genome-wide DNA microarray datasets of bacterial gene expression under simulated dormancy conditions. Subcellular localisation of M. tuberculosis proteins encoded by genes, was subsequently carried out on the entire genome to identify vaccine targets.

[0590]Briefly, experimental conditions in the dormancy models were quite varied so ...

example 2

Rv2386c Epitope Identification

Method

[0598]T cell epitope prediction was based on the following approaches:

PredictionNameURL / ReferencesCD4 andMultipredwebsite: antigen.i2r.a-star.edu.sg / multipred / CD8Zhang, G. L., Khan, A. M., Srinivasan, K. N., August, J. T. andBrusic, V. (2005) “MULTIPRED: a computational system forprediction of promiscuous HLA binding peptides” NucleicAcids Res. 33, W172-W179.SVMHCwebsite: www-bs.informatik.uni-tuebingen.de / SVMHC“Prediction of MHC class I binding peptides, using SVMHC.”Pierre Dönnes and Arne Elofsson in: BMC Bioinformatics2002 3: 25CD4ProPredwebsite: www.imtech.res.in / raghava / propred / Singh, H. and Raghava, G. P. S.(2001) “ProPred: Prediction ofHLA-DR binding sites.”Bioinformatics, 17(12), 1236-37.Tepitope2In house program based on:H. Bian, J. Hammer (2004) “Discovery of promiscuous HLA-II-restricted T cell epitopes with TEPITOPE.” Methods 34: 468-75CD8nHLAwebsite: www.imtech.res.in / raghava / nhlapred / Bhasin M. and Raghava G P S (2006) “A hybrid appro...

example 3

H37Rv Homologues

[0601]Rv2386c sequences from a number of M. tuberculosis strains and BCG were identified using BLASTP searches of GenBank (H37Rv reference sequence accession number YP—177877.1

StrainAccession Number% identityCDC1551NP_336935.1100F11YP_001288342.1100HaarlemZP_02247771.1100CZP_00878160.199BCGCAL72388.1100

[0602]Alignment of the homologue sequences indicates a high level of identity.

Biological Assays

Quantification of T Cell Responses to Rv2386c

[0603]Polypeptides may be screened for their ability to activate T-cells (induction of proliferation and / or production of cytokines) in peripheral blood mononuclear cell (PBMC) or in whole blood preparations from infected (such as latently infected) individuals.

[0604]Latently infected individuals are usually identified by a skin test that has a diameter above 10 mm and without symptoms, with no Mtb positive culture, with a negative sputum negative and with no lesion (as detected by chest X-Ray).

[0605]A range of in vitro assays can ...

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Abstract

The present invention is directed to a polypeptide which comprises: (i) an Rv2386c protein sequence; (ii) a variant of an Rv2386c protein sequence; or (iii) an immunogenic fragment of an Rv2386c protein sequence. In other aspects the invention is directed to associated polynucleotides, fusion proteins and methods for the treatment or prevention of tuberculosis.

Description

FIELD OF THE INVENTION[0001]The present invention relates to polypeptides and polynucleotides for use in the treatment or prevention of tuberculosis, in particular for use in the treatment or prevention of latent tuberculosis and in the prevention or delay of reactivation of tuberculosis (and also to related methods). The present invention further relates to pharmaceutical and immunogenic compositions comprising said polypeptides and polynucleotides, and to methods for the diagnosis of tuberculosis (in particular latent tuberculosis).BACKGROUND OF THE INVENTION[0002]Tuberculosis (TB) is a chronic infectious disease caused by infection with Mycobacterium tuberculosis and other Mycobacterium species. It is a major disease in developing countries, as well as an increasing problem in developed areas of the world. More than 2 billion people are believed to be infected with TB bacilli, with about 9.2 million new cases of TB and 1.7 million deaths each year. 10% of those infected with TB b...

Claims

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Application Information

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IPC IPC(8): A61K39/04C07K19/00C07H21/00A61P31/06A61P37/04
CPCA61K38/00A61K39/04A61K2039/53A61K2039/55555C12N9/90A61K2039/55577C07K14/35C12N9/88A61K2039/55572C07K16/1289G01N33/5695C07K2319/00A61P31/06A61P37/04A61P43/00C07K7/06
Inventor BROWN, JAMESMETTENS, PASCALMURPHY, DENNIS
Owner GLAXO GROUP LTD
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