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Induction of immune responses to isoaspartyl-modified antigens

a technology of isoaspartyl and immunomodulatory protein, which is applied in the field of tumor treatment and bacterial or viral pathogen pathogen treatment, can solve the problems of unambiguous linkage of no pathogen and imperfect tolerance to self-antigens, and achieve the effect of enhancing the immune response of a patien

Active Publication Date: 2009-12-24
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is directed to a method of enhancing the immune response of a patient relative to the normal immune response. This is achieved by growing cells containing a tumor antigen, a bacterial protein, or a viral protein, and converting an aspartic acid residue or an asparigine residue in the tumor antigen, bacterial protein, or viral protein to an isoaspartic acid residue. The isoaspartic acid-containing tumor antigen, bacterial protein, or viral protein is then administered to the patient to enhance the immune response. The invention also includes a peptide comprising a portion of the tumor antigen, bacterial protein, or viral protein that contains an aspartic acid residue or an asparigine residue, which is then converted to an isoaspartic acid residue to enhance the immune response. The invention also includes a vaccine and an antibody that is reactive with a protein or fragment thereof that contains an isoaspartic acid residue.

Problems solved by technology

Despite the efforts to instruct the immune system to ignore self-tissues, the appearance of various autoimmune diseases demonstrates that tolerance to self-antigens is not perfect.
However, no pathogen has been unambiguously linked with the induction of any human autoimmune syndrome.

Method used

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  • Induction of immune responses to isoaspartyl-modified antigens
  • Induction of immune responses to isoaspartyl-modified antigens
  • Induction of immune responses to isoaspartyl-modified antigens

Examples

Experimental program
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Effect test

example 1

Aged Proteins Show High Levels of Isoaspartyl Residues

[0070]A model protein, pigeon cytochrome c (PCC) and crude tumor cell lysates in PBS were incubated at 37° C. for 21 days and exposed to 5% carbon dioxide. Following treatment, the protein was assayed for the presence of isoaspartyl modifications in comparison with untreated proteins as described above. As shown in FIG. 1, aged proteins possess from two to four times the molarity of isoaspartyl modifications as compared to control proteins.

example 2

Acid-Methanol Treatment of B16 Tumor Cell Lysates Enhances the Level of Isoaspartyl Modification

[0071]B16 tumor cells were lysed in phosphate buffered saline (PBS) and subjected to HCl-methanol treatment or untreated (in PBS) as described above. Five μg of protein was then assayed for the presence of isoaspartyl modification. As shown in FIG. 2, acid-methanol raised the isoaspartyl content of tumor protein nearly 20 fold as compared to untreated tumor lysate protein.

example 3

Adenosine Dialdehyde Treatment of Living B16 Melanoma Cells Enhances Isoaspartyl Content in Tumor Proteins

[0072]In cell culture, B16 cells were incubated with 30 μM adenosine dialdehyde for 48 h as described above. Cells were then harvested and lysed in PBS. Isoaspartyl content was determined as described above. As shown in FIG. 3, isoaspartyl content was enhanced from two to five fold compared to untreated B16 cells.

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Abstract

The present invention is directed to a method of enhancing the immune response of a patient relative to the normal immune response, by administering isoaspartyl-modified proteins, peptides, or cells, to a patient. The present invention is also directed to vaccines containing the isoaspartyl-modified proteins, peptides, or cells, as well as antibodies reactive with the isoaspartyl-modified proteins, peptides, or cells.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation-in-Part of International Application No. PCT / US02 / 00336, filed Jan. 4, 2002, which claims the benefit of U.S. Provisional Application No. 60 / 259,765 filed Jan. 4, 2001. These applications are herein incorporated by reference in their entireties.STATEMENT OF GOVERNMENT SUPPORT[0002]This application was made with United States Government support under Award Numbers AI36529; 5RO1 AI-48120-03; 1R41 DK-064528-01; and 1R41 CA101542-01, all from the National Institutes of Health. The U.S. Government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]This invention relates to methods of treating tumors and bacterial or viral pathogens, and more particularly to methods of treating tumors and bacterial or viral pathogens using isoaspartyl-modified proteins to enhance immune response. The invention also relates to vaccines and antibodies used in these treatments.[00...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/12A61K39/00A61K39/02A61P35/00
CPCA61K39/00A61K2039/5152A61K39/0011A61P35/00Y02A50/30
Inventor MAMULA, MARK J.
Owner YALE UNIV