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DNA vaccines encoding heat shock proteins

a technology of heat shock protein and dna vaccine, which is applied in the direction of immunological disorders, antibody medical ingredients, peptide/protein ingredients, etc., can solve the problem of limiting the frequency of administration of the therapeutic composition needed to treat an animal, and achieve the effect of limiting the frequency of administration of the therapeutic composition

Inactive Publication Date: 2005-09-08
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is related to a new technology for treating T-cell-mediated inflammatory autoimmune diseases. This technology involves using DNA vaccines that encode heat shock proteins to elicit protective immunity against these diseases. The heat shock proteins are mammalian proteins that are highly conserved and have been shown to be effective in treating other autoimmune diseases. The DNA vaccines can be administered repeatedly over a long period of time, as they provide long-term expression of the encoded polypeptides. The invention also includes recombinant constructs and pharmaceutical compositions containing the DNA vaccines for treating T-cell-mediated inflammatory autoimmune diseases.

Problems solved by technology

Such long-term expression allows for the maintenance of an effective, but non-toxic, dose of the encoded polypeptides to treat the disease and limits the frequency of administration of the therapeutic composition needed to treat an animal.

Method used

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  • DNA vaccines encoding heat shock proteins
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Examples

Experimental program
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Effect test

example 1

HSP60 DNA Fragments Inhibit AA

[0103] To learn whether fragments of HSP60 DNA could inhibit AA, the cDNA corresponding to the human hsp60 gene was divided into five fragments, each with a 30 pb overlap, and each was cloned into the pcDNA3 vector (Table II). In this way, five constructs corresponding to HSP60-derived fragments were generated overlapping by 10 aa: pI, aa 1-140; pII, aa 130-260; pIII, aa 250-410, pIV, aa 400-470 and pV, aa 460-540 (Table II. Lewis rats were vaccinated with one of the HSP60 fragment constructs or with pcDNA3 as a control, and AA was induced. FIG. 1A shows that the rats vaccinated with pI or pII manifested significantly decreased arthritis compared to rats vaccinated with constructs pIII, pIV or pV or with control pcDNA3. The protective effect of the vaccination with constructs pI and pII was also reflected by a significant reduction in ankle swelling (FIG. 1B), and by a reduction of the mean maximal score, which was lower in those rats vaccinated with p...

example 2

In Vitro Proliferation of LNC Isolated from pHSP60- or PI-Vaccinated Rats in Response to Various HSP60 Peptides

[0104] To learn whether the suppression of AA by DNA vaccination with pHSP60, pI or pII was associated with T-cell reactivity to a specific HSP60 epitope, the proliferation (Stimulation Index, SI) of LNC isolated from pHSP60-vaccinated rats was studied in response to a panel of overlapping peptides spanning the region of human HSP60 encoded by pI and pII (aa 1-275; Table I). Controls were LNC prepared from rats vaccinated with pcDNA3 or pHSP65 and challenged with Mt suspended in IFA to induce AA. FIG. 2A shows that only peptide Hu3 (aa 31-50 of human HSP60) induced a significant response in LNC taken from pHSP60-vaccinated rats; cells prepared from pHSP65 or pcDNA-vaccinated rats did not respond to Hu3. Note that the sequence of the HSP60 protein in the region 31-50 is identical in rat and human HSP60; thus Hu3 is a self-peptide (Table III). FIG. 2B shows a dose-dependant ...

example 3

Peptide Hu3 Inhibits AA

[0105] To establish a link between the immune response to Hu3 and prevention of AA, rats were vaccinated with Hu3, or with its mycobacterial counterpart Mt3 (Table III) or with Hu12 (Table I) as controls. Each rat received a single i.p. dose of 100 μg of peptide in IFA seven days (day-7) before the induction of AA (day 0). FIG. 3A shows that the Hu3-vaccinated rats developed significantly decreased disease compared to non-immunized rats or rats vaccinated with PBS, Hu12 or Mt3. This reduction in AA was also reflected by a significant reduction in ankle swelling (14.2±4.7 in Hu3-vaccinated rats vs 32.2±3.5 in PBS / IFA-vaccinated rats, p=0.02; FIG. 3B). Therefore, vaccination with Hu3 prevents AA.

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Abstract

The present invention is related to recombinant constructs encoding heat shock proteins or active fragments thereof that are effective in treating T cell mediated inflammatory autoimmune diseases by DNA vaccines. The treatment with the recombinant constructs of the present invention provides long-term expression of specific heat shock proteins for fragments thereof. In one embodiment, the present invention is related to a recombinant construct of a nucleic acid sequence encoding HSP60, HSP70 or HSP90. The present invention also is related to a recombinant construct of a nucleic acid sequence selected from amino acids 1-140 of HSP60, amino acids 130-260 of HSP60 and amino acids 31-50 of HSP60. Another aspect of the present invention is related to an active fragment of HSP60 corresponding to amino acids 31-50 of HSP60 effective in treating arthritis.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of International application PCT / IL03 / 00417 filed May 21, 2003, which claims priority to U.S. provisional patent application No. 60 / 381,821 filed May 21, 2002, the entire content of which is expressly incorporated herein by reference thereto.FIELD OF THE INVENTION [0002] The present invention relates to recombinant constructs encoding heat shock proteins or active fragments thereof, effective in treating T cell mediated diseases including inflammatory autoimmune diseases by DNA vaccination. The present invention further relates to compositions and methods for treating T cell mediated diseases. BACKGROUND OF THE INVENTION [0003] While the normal immune system is closely regulated, aberrations in immune responses are not uncommon. In some instances, the immune system functions inappropriately and reacts to a component of the host as if it were, in fact, foreign. Such a response results in an autoimmune d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61KA61K38/17A61K39/00A61K48/00
CPCA61K38/1709A61K39/00A61K31/7088A61K2039/53A61K39/0008A61P29/00A61P37/06A61K39/46A61K39/46433A61K39/4621A61K2239/31A61K39/4611A61K2239/38A61K48/00A61K2039/54A61K2039/545A61K2039/57
Inventor COHEN, IRUNQUINTANA, FRANCISCOCARMI, PNINAMOR, FELIX
Owner YEDA RES & DEV CO LTD
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