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Induction of immune responses to isoaspartyl-modified antigens

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Title: Induction of immune responses to isoaspartyl-modified antigens.
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. ...


USPTO Applicaton #: #20090317416 - Class: 4241861 (USPTO) - 12/24/09 - Class 424 
Drug, Bio-affecting And Body Treating Compositions > Antigen, Epitope, Or Other Immunospecific Immunoeffector (e.g., Immunospecific Vaccine, Immunospecific Stimulator Of Cell-mediated Immunity, Immunospecific Tolerogen, Immunospecific Immunosuppressor, Etc.) >Amino Acid Sequence Disclosed In Whole Or In Part; Or Conjugate, Complex, Or Fusion Protein Or Fusion Polypeptide Including The Same >Disclosed Amino Acid Sequence Derived From Virus

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The Patent Description & Claims data below is from USPTO Patent Application 20090317416, Induction of immune responses to isoaspartyl-modified antigens.

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CROSS-REFERENCE TO RELATED APPLICATIONS

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

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

1. Field of the Invention

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.

2. Brief Description of the Related Art

The immune system has evolved to be tolerant of self-proteins by the deletion of autoreactive cells in the thymus or bone marrow and by the establishment of B and T lymphocyte anergy in the peripheral circulation (Billingham, R. E. et al., Nature 172:603-606, 1956; Schlid, H. et al., Science 247:587-589, 1990). These mechanisms are based on the presentation of a vast array of self-peptides to the lymphoid repertoire. 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. Flaws in the development of immune tolerance can be revealed by the immunization of animal models with a variety of self-peptides leading to B and T cell autoimmunity as well as autoimmune-mediated pathology (Lehman, P. V. et al., Nature 358:155-157, 1992; Mamula, M. J., J. Exp. Med. 177:567-571, 1993; Bockenstedt, L. K., et al., J. Immunol. 154:3516-3524, 1995).

How tolerance is broken in the initiation of autoimmunity is not completely understood. The immunization of mice with a single self-peptide, the amino-terminal 11 amino acids of myelin basic protein (MBP) in complete Freund\'s adjuvant can elicit pathology resembling that of human multiple sclerosis (Lehman, P. V. et al., Nature 358:155-157, 1992). The induction of disease requires a post-translationally acetylated form of MBP peptide 1-11. While this disease can be elicited with a single self-peptide or event with T cells of a single specificity, the autoimmune response diversifies to many sites on the MBP over the course of the disease. T cell responses originate with the dominant single self peptide but rapidly evolve to include other cryptic peptide epitopes within MBP. Similar observations of determinant spreading have been made in murine models of diabetes and systemic lupus erythematosus (SLE), two diseases arising spontaneously in susceptible strains of mice (Kaufman, D. L. et al., Nature 366:69-72, 1993; Bockenstedt, L. K., et al., J. Immunol. 154:3516-3524, 1995); Fatenejad, S. et al., J. Immunol. 152:5523-5531, 1994).

Antinuclear antibodies specific for double-stranded DNA and the U1/Sm ribonucleoprotein particle (snRNP) are diagnostic markers of SLE. The snRNP particle is an RNA-protein complex essential for the splicing of pre-mRNA (Wassarman, D. A. et al., Science 257:1918-1925, 1992). Proteins designated B, B′, and D comprise the target proteins of anti-Sm autoantibodies in SLE patients. It is not known how high affinity autoantibodies and autoreactive T cells arise to these intracellular proteins the mature phenotype of autoantibodies found in diseases such as SLE indicates that autoimmunity is driven by helper T lymphocytes and a source of antigen (Steinberg, A. D., et al., J. Immunol. 125:871-873, 1980; Jevnikar, A. M. et al., J. Exp. Med. 179:1137-1143, 1988; Tan, E. M. Adv. Immunol. 44:93-151, 1989).

While it is clear that autoimmunity can spread to several sites on an autoantigens over the course of experimentally induced disease models, the initiating antigenic peptide in naturally arising disease is unknown. A hypothesis of molecular mimicry implies that foreign pathogens that share amino acid sequences with self-peptides can break immunologic tolerance in the induction of autoimmunity. However, no pathogen has been unambiguously linked with the induction of any human autoimmune syndrome. Alternatively, the present inventors have initiated studies to consider forms of self-antigens that can be viewed as foreign by the immune system. The immune system does not respond to immunization with selected peptides from self-proteins. However, when the same self-peptides are converted to the isoaspartyl isoform, vigorous autoimmune responses develop upon immunization. After initiation by the isoaspartyl peptide isoforms, autoimmunity is amplified to other peptides on the autoantigen.

Isoaspartyl peptides arise spontaneously under physiologic conditions and are particularly elevated in cells undergoing stress and in aging cells. The presence of isoaspartyl peptides have been observed as a major component of the amyloid-containing brain plaques of patients with Alzheimer\'s disease. With relevance to immune responses, it is possible that tolerance to these forms of self proteins fails to occur early in lymphocyte development. Based on the enhanced immunity to some isoaspartyl self-peptides, it is possible that an accumulation of these aberrant peptides may be an early stimulus for autoimmune responses.

The present inventors have previously shown that isoaspartyl modifications of “self” proteins (e.g., proteins recognized by a cell as it\'s own) can result in autoimmunity. In these studies, it was shown that autoimmunity could be generated to isoaspartyl-modified self proteins, such as cytochrome c, while the identical unmodified protein would elicit no response from the immune system (Mamula, M. J. et al., J. Biol. Chem. 274:22321-22327, 1999). Applications of this phenomenon, however, were not disclosed.

Tumor antigens are considered a form of self protein to which little immune responses are generally elicited. This lack of immunity allows the tumor cells to proliferate and spread without the interference of immune responses that may attack and destroy the tumor cell. In a similar manner, many proteins on the surfaces of viral particles (such as gp proteins on the surface of HIV) are only weakly antigenic in eliciting responses of the immune system. These properties of viral and bacterial proteins allow for their survival in the host.

What is needed in the art is a method of identifying the weakly antigenic proteins found on tumors, bacteria and viruses, and a vaccine and antibody that can select and eliminate these weakly antigenic species. The present invention is believed to be an answer to that need.

SUMMARY

OF THE INVENTION

In one aspect, the present invention is directed to a method of enhancing the immune response of a patient relative to the normal immune response, comprising the steps of: growing cells containing a tumor antigen, a bacterial protein, or a viral protein under conditions wherein an aspartic acid residue or an asparigine residue in the tumor antigen, the bacterial protein, or the viral protein is converted to an isoaspartic acid residue to produce an isoaspartic acid-containing tumor antigen, an isoaspartic acid-containing bacterial protein, or an isoaspartic acid-containing viral protein; optionally isolating the isoaspartic acid-containing tumor antigen, an isoaspartic acid-containing bacterial protein, or an isoaspartic acid-containing viral protein; and administering the cells or the isolated isoaspartic acid-containing tumor antigen, an isoaspartic acid-containing bacterial protein, or an isoaspartic acid-containing viral protein to the patient to enhance the immune response of the patient.

In another aspect, the present invention is directed to a method of enhancing the immune response of a patient relative to the normal immune response, comprising the steps of: administering to the patient a peptide comprising 9-40 amino acid residues of a tumor antigen, a bacterial protein, or a viral protein, wherein the peptide comprises an aspartic acid residue or an asparigine residue that has been replaced with an isoaspartic acid residue, to enhance the immune response of the patient.

In another aspect, the present invention is directed to a method of enhancing the immune response of a patient relative to the normal immune response, comprising the steps of: providing a tumor antigen, a bacterial protein, or a viral protein, or a fragment thereof, wherein each of the tumor antigen, bacterial protein, or viral protein, or fragment thereof, comprises an aspartic acid residue or an asparigine residue; treating the tumor antigen, bacterial protein, or viral protein, or fragment thereof, to convert the aspartic acid residue or the asparigine residue to an isoaspartic acid residue to produce an isoaspartic acid-containing tumor antigen, an isoaspartic acid-containing bacterial protein, or an isoaspartic acid-containing viral protein, or fragments thereof; and administering the isoaspartic acid-containing tumor antigen, the isoaspartic acid-containing bacterial protein, or the isoaspartic acid-containing viral protein, or fragments thereof, to the patient to elicit the enhanced immune response.

In another aspect, the present invention is directed to a vaccine, comprising a protein or fragment thereof, the protein selected from the group consisting of tumor antigens, bacterial proteins, viral proteins, and combinations thereof, the protein or fragment thereof comprising an isoaspartic acid residue; and a pharmaceutically acceptable carrier.

In another aspect, the present invention is directed to an antibody reactive with a protein or fragment thereof, the protein or fragment thereof comprising an isoaspartic acid residue, the protein or fragment thereof selected from the group consisting of tumor antigens, bacterial proteins, viral proteins, and combinations thereof.

These and other aspects will become apparent upon reading the following detailed description of the invention.



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stats Patent Info
Application #
US 20090317416 A1
Publish Date
12/24/2009
Document #
File Date
04/25/2014
USPTO Class
Other USPTO Classes
International Class
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Antigen
Immune Response
Induction
Vaccine
Vaccines


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