Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Fusion protein or fusion polypeptide
Reexamination Certificate
2000-09-12
2003-05-13
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Fusion protein or fusion polypeptide
C424S085100, C424S184100, C424S185100, C424S277100, C424S278100, C530S350000, C530S351000, C530S395000, C530S806000, C514S001000, C514S002600, C514S008100, C514S885000
Reexamination Certificate
active
06562347
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a vaccine that treats cancer as well as a vaccine that treats or prevents human immunodeficiency virus (HIV) infection. In particular, the present invention provides a fusion polypeptide comprising a chemokine and either a tumor or viral antigen which is administered as either a protein or nucleic acid vaccine to elicit an immune response effective in treating cancer or effective in treating or preventing HIV infection.
2. Background Art
Tumor cells are known to express tumor-specific antigens on the cell surface. These antigens are believed to be poorly immunogenic, largely because they represent gene products of oncogenes or other cellular genes which are normally present in the host and are therefore not clearly recognized as nonself. Although numerous investigators have tried to target immune responses against epitopes from various tumor specific antigens, none have been successful in eliciting adequate tumor immunity in vivo (71).
Humans are particularly vulnerable to cancer as a result of an ineffective immunogenic response (72). In fact, the poor immunogenicity of relevant cancer antigens has proven to be the single greatest obstacle to successful immunotherapy with tumor vaccines (73). Over the past 30 years, literally thousands of patients have been administered tumor cell antigens as vaccine preparations, but the results of these trials have demonstrated that tumor cell immunization has failed to provide a rational basis for the design or construction of effective vaccines. Even where patients express tumor-specific antibodies or cytotoxic T-cells, this immune response does not correlate with a suppression of the associated disease. This failure of the immune system to protect the host may be due to expression of tumor antigens that are poorly immunogenic or to heterologous expression of specific antigens by various tumor cells. The appropriate presentation of tumor antigens in order to elicit an immune response effective in inhibiting tumor growth remains a central issue in the development of an effective cancer vaccine.
Chemokines are a group of usually small secreted proteins (7-15 kDa) induced by inflammatory stimuli and are involved in orchestrating the selective migration, diapedesis and activation of blood-born leukocytes that mediate the inflammatory response (23,26). Chemokines mediate their function through interaction with specific cell surface receptor proteins (23). At least four chemokine subfamilies have been identified as defined by a cysteine signature motif, termed CC, CXC, C and CX
3
C, where C is a cysteine and X is any amino acid residue. Structural studies have revealed that at least both CXC and CC chemokines share very similar tertiary structure (monomer), but different quaternary structure (dimer) (120-124). For the most part, conformational differences are localized to sections of loop or the N-terminus.
Monocyte chemotactic protein-3 (MCP-3) is a potent chemoattractant of monocytes and dendritic cells, T lymphocytes, basophils and eosinophils (10, 23, 26, 37).
There remains a great need for a method of presenting tumor antigens, which are known to be poorly immunogenic, “self” antigens to a subject's immune system in a manner that elicits an immune response powerful enough to inhibit the growth of tumor cells in the subject. This invention overcomes the previous limitations and shortcomings in the art by providing a fusion protein comprising a chemokine and a tumor antigen which can produce an in vivo immune response, resulting in the inhibition of tumor cells. This invention also overcomes previous shortcomings in the field of HIV vaccine development by providing a fusion protein comprising a chemokine and an HIV antigen which is effective as a vaccine for treating or preventing HIV infection.
SUMMARY OF THE INVENTION
The present invention provides a fusion polypeptide comprising human monocyte chemotactic protein-3 and human Muc-1, a fusion polypeptide comprising human interferon-induced protein 10 and human Muc-1, a fusion polypeptide comprising human macrophage-derived chemokine and human Muc-1 and a fusion polypeptide comprising human SDF-1 and human Muc-1.
The present invention also provides a fusion polypeptide comprising a human chemokine and a human immunodeficiency virus (HIV) antigen, wherein the chemokine can be IP-10, MCP-1, MCP-2, MCP-3, MCP-4, MIP 1, RANTES, SDF-1, MIG and/or MDC and wherein the HIV antigen can be gp120, gp160, gp41, an active fragment of gp120, an active fragment of gp160 and/or an active fragment of gp41.
In addition, the present invention provides a method of producing an immune response in a subject, comprising administering to the subject any of the fusion polypeptides of this invention, comprising a chemokine and a human immunodeficiency virus (HIV) antigen, or a chemokine and a tumor antigen, either as a protein or a nucleic acid encoding the fusion polypeptide.
Also provided is a method of treating a cancer in a subject comprising adminstering to the subject any of the fusion polypeptides of this invention, comprising a chemokine and a tumor antigen, either as a protein or a nucleic acid encoding the fusion polypeptide.
Further provided is a method of treating or preventing HIV infection in a subject, comprising administering to the subject any of the fusion polypeptides of this invention, comprising a chemokine and a human immunodeficiency virus (HIV) antigen, either as a protein or a nucleic acid encoding the fusion polypeptide.
A method of treating a B cell tumor in a subject is also provided, comprising administering to the subject a fusion polypeptide comprising a human chemokine and a B cell tumor antigen.
Various other objectives and advantages of the present invention will become apparent from the following detailed description.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used in the claims, “a” can include multiples. For example, “a cell” can mean a single cell or more than one cell.
The present invention is based on the unexpected discovery that the administration of a fusion protein comprising a chemokine and a tumor antigen or administration of a nucleic acid encoding a fusion protein comprising a chemokine and a tumor antigen yields an effective and specific anti-tumor immune response by converting a “self” tumor antigen into a potent immunogen by binding to a chemokine moiety. A further unexpected discovery of the present invention is that the chemokine-scFv fusion polypeptide of this invention is superior to the prototype Id-KLH vaccine in tumor protection studies as described herein.
Thus, the present invention provides a fusion polypeptide comprising a chemokine and a tumor antigen. The fusion polypeptide can be present in a purified form and can induce an immune response against the tumor antigen and inhibit the growth of tumor cells expressing the tumor antigen. “Purified” as used herein means the polypeptide is sufficiently free of contaminants or cell components with which proteins normally occur to allow the peptide to be used therapeutically. It is not contemplated that “purified” necessitates having a preparation that is technically totally pure (homogeneous), but purified as used herein means the fusion polypeptide is sufficiently pure to provide the polypeptide in a state where it can be used therapeutically. As used herein, “fusion polypeptide” means a polypeptide made up of two or more amino acid sequences representing peptides or polypeptides from different sources. Also as used herein, “epitope” refers to a specific amino acid sequence of limited length which, when present in the proper conformation, provides a reactive site for an antibody or T cell receptor. The identification of epitopes on antigens can be carried out by immunology protocols that are standard in the art (74). As further used herein, “tumor antigen” describes a polypeptide expressed on the cell surface of specific tumor cells and which can serve to identify the type of tumor. An epitope of the tumor antigen can
Biragyn Arya
Kwak Larry W.
Gambel Phillip
Needle & Rosenberg, PC.
Roark Jessica H.
The United States of America as represented by the Department of
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