Stress proteins and uses therefor

a stress protein and protein technology, applied in the field of stress proteins and uses therefor, can solve the problems of presenting a significant global health problem, and achieve the effects of reducing or preventing the adverse effects of cancer cells, provoking immune tolerance against the selected stress protein, and provoking immune toleran

Inactive Publication Date: 2005-07-28
WHITEHEAD INST FOR BIOMEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] Preventing or reducing adverse effects of viral pathogens which do or do not contain stress proteins, as well as preventing or reducing the adverse effects of cancer cells according to the present method, is effected by enhancing an individual's immune surveillance system. Enhancement of immune response can be effected by modulating the immune cells by stimulation with a stress protein (e.g., a bacterial stress protein).
[0012] A selected stress protein of the present invention can be administered to an individual, according to the method of the present invention, and result in an immune response which provides protection against subsequent infection by a pathogen (e.g., bacteria, other infectious agents which produce stress proteins) or reduction or prevention of adverse effects of cancer cells. Alternatively, a selected stress protein can be administered to an individual, generally over time, to induce immune tolerance against the selected stress protein. For example, a selected stress protein can be administered in multiple doses over time in order to induce immune tolerance against an autoimmune disease such as rheumatoid arthritis.

Problems solved by technology

These diseases afflict 20-30 million people and continue to present a significant global health problem.

Method used

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  • Stress proteins and uses therefor
  • Stress proteins and uses therefor
  • Stress proteins and uses therefor

Examples

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example 1

Isolation and Characterization of Mycobacterial Stress Protein Antigens

Recombinant DNA Clones

[0054] The isolation and characterization of M. tuberculosis and M. leprae λgtll genomic DNA clones with murine monoclonal antibodies have been described. Husson, R. N. and Young, R. A., Proc. Natl. Acad. Sci., USA 84: 1679-1683 (1987); Young, R. A., et al., Nature (London) 316: 450-452 (1985). DNA was isolated from these clones and was manipulated by standard procedures. Davis, R. W., Advanced Bacterial Genetics: A Manual for Genetic Engineering (Cold Spring Harbor Lab., Cold Spring Harbor, N.Y.), (1980).

DNA Sequence Analysis.

[0055] DNA was subcloned into vector M13 mp18 or M13 mp19 (New England Biolabs), as suggested by the supplier. Dideoxynucleotide chain-termination reactions and gel electrophoresis of the sequenced produced were as described. Davis, R. W., Advanced Bacterial Genetics: A Manual for Genetic Engineering (Cold Spring Harbor Lab., Cold Spring Harbor, N.Y.), (1980). DN...

example 2

Construction of Stress Protein-Fusion Vaccines for Use as Adjuvant-Free Carriers in Immunizations

Recombinant Fusion Vectors

[0070] A series of stress protein fusion vectors for use in E. coli were constructed and are shown in FIG. 5. These vectors contain the T7 RNA polymerase promoter fused to the M. bovis BCG hsp70 gene or the M. bovis BCG hsp60 gene. The vectors also contain a polylinker with multiple cloning sites, permitting incorporation of a gene of interest so that the antigen encoded by that gene is expressed as a fusion protein with the stress protein. A subset of these vectors permit incorporation of the foreign gene with a coding sequence for a C-terminal 6-Histidine “tag” for ease of fusion protein purification. Thus far, recombinant clones have been generated that produce hsp70 proteins fused to HIV gag and HIV pol proteins.

Purification of Stress Protein Fusions.

[0071] Two strategies have been developed to purify the recombinant fusion proteins. The T7 system usua...

example 3

Adjuvant-Free Carrier Effect of HSP70 In Vivo

[0072] The stress protein fusion vector pKS70 (FIG. 6), containing the T7 RNA polymerase promoter, a polylinker and the mycobacterial tuberculosis hsp70 gene, was constructed. The HIV p24 gag gene was subcloned into pKS70 using the Ndel and BamHI sites and the resulting pKS72 vector (FIG. 6) was used to produce the p24-hsp70 fusion protein in E. coli. The fusion protein was purified as inclusion bodies and further purified using ATP-agarose chromatography and MonoQ ion exchange chromatography.

[0073] The p24-hsp70 protein in phosphate buffered saline (PBS), in the absence of an adjuvant, was injected intraperitoneally into Balb / c mice. As controls, the p24 protein alone in PBS or the hsp70 protein alone in PBS was injected into different groups of mice. Three weeks later, the mice were boosted and finally, three weeks after the boost, the mice were bled. The anti-p24 antibody titer was then determined by ELISA. Mice injected with 25 pmol...

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Abstract

The present invention relates to stress proteins and methods of modulating an individual's immune response. In particular, it relates to the use of such stress proteins in immune therapy and prophylaxis, which results in an induction or enhancement of an individual's immune response and as an immunotherapeutic agent which results in a decrease of an individual's immune response to his or her own cells. The present invention also relates to compositions comprising a stress protein joined to another component, such as a fusion protein in which a stress protein is fused to an antigen. Further, the present invention relates to a method of generating antibodies to a substance using a conjugate comprised of a stress protein joined to the substance.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 10 / 046,649, filed Jan. 14, 2002, which is a divisional of U.S. application Ser. No. 08 / 336,251, filed Nov. 3, 1994, now U.S. Pat. No. 6,338,952 B1, which is a continuation-in-part of the corresponding International Application PCT / US94 / 06362, filed Jun. 6, 1994 and U.S. Ser. No. 08 / 073,381, filed Jun. 4, 1993, now abandoned, which is a Continuation-in-Part of U.S. Ser. No. 07 / 804,632 filed Dec. 9, 1991, now abandoned, which is a File-Wrapper-Continuation of U.S. application Ser. No. 07 / 366,581 filed Jun. 15, 1989, now abandoned, which is a Continuation-in-Part of U.S. application Ser. No. 07 / 207,298 filed Jun. 15, 1988, now abandoned, and the corresponding International Application PCT / US89 / 02619 filed Jun. 15, 1989. The entire teachings of the above applications are incorporated herein by reference. GOVERNMENT SUPPORT [0002] Work described herein was funded by grants from the National Instit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/00A61K39/02C12N15/09A61K39/04A61K39/12A61K39/21A61K39/295A61K39/385A61K39/39A61P37/00C07K14/00C07K14/155C07K14/16C07K14/35C07K14/37C07K14/44C07K19/00C12N15/62C12P21/02C12P21/04
CPCA61K39/00A61K2039/545A61K39/04A61K39/21A61K39/385A61K39/39A61K2039/55516A61K2039/6043C07K14/005C07K14/35C07K2319/03C07K2319/20C07K2319/21C07K2319/35C07K2319/40C07K2319/50C07K2319/735C07K2319/75C12N15/62C12N2740/16222C12N2740/16234A61K39/12A61K2039/70A61K39/0008A61P37/00
Inventor YOUNG, RICHARDYOUNG, DOUGLAS
Owner WHITEHEAD INST FOR BIOMEDICAL RES
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