Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
1998-07-10
2003-09-23
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S277100, C424S278100, C514S015800, C514S885000, C514S016700
Reexamination Certificate
active
06623740
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of immunology. In particular, it relates to peptides which form complexes with HLA molecules, and exhibit a half-life of more than 30 minutes relative to degradation by peptidase. More particularly, the present invention contemplates a class of peptides of a particular nonapeptide, MZ2-E, which have been modified to resist peptidase degradation. The contemplated peptides are useful in many ways, e.g., as immunogens and as materials which target and bind MHC/HLA molecules.
BACKGROUND AND PRIOR ART
The study of the recognition or lack of recognition of foreign antigen by a host organism has proceeded in many different directions. Understanding of the field presumes some understanding of both basic immunology, and protein chemistry.
The immune system is constantly at war, fighting viruses, bacteria, and other pathogens that try to invade the body. In this war, it uses a diverse range of effectors in order to deal with the threat to health posed by an equally diverse range of infectious organisms that are prevalent in the environment. For example, T-lymphocytes play a central role in the induction and regulation of the immune response and in the execution of immunological functions. These cells are particularly important in tumor rejection and in fighting viral infections.
However, antigen recognition by the T-lymphocytes is restricted by cell-surface glycoproteins encoded by the highly polymorphic genes of the major histocompatibility complex (MHC) molecules. This discrimination requires a T cell specific for a particular combination of an HLA molecule and a peptide rather than the intact foreign antigen itself. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. Much work has focused on the mechanisms by which proteins are processed into the HLA binding peptide. See, in this regard, Cresswell, Nature 343: 593-594 (1990); Aichinger, et al. Biochemical Society Trans, 23: 657-659, (1995); Fremont et al., Science 257: 919 (1992); and Lanzavecchia, Science 260:937-943 (1993); Matsumura et al., Science 257: 927 (1992); Latron et al., Science 257: 964 (1992).
MHC class I molecules are expressed by almost all nucleated cells of the body and, in the main, present peptides derived from intracellular proteins to cytotoxic T cells expressing the CD8 co-receptor. Activation of the cytotoxic T cell, in turn, results in the destruction of the target cells by apoptosis induced by perforin/granzyme and/or Fas ligand.
In the case of MHC class I molecules, the peptide fragments usually contain from 8 to 11 amino acids and are generated inside the antigen presenting cells by a complex machinery involving proteases, peptide transporters and molecular chaperones. See Roitt, et al.
Immunology
(Mosby-Year Book Europe, 1993).
Although intact proteins need to be processed to generate antigenic peptide, soluble peptides are also known to directly bind to small fractions of empty MHC class I or II molecules present on cell surfaces. See in this regard, Braciale & Braciale, Immunology Today, 12(4): 124-129 (1991); Elliot, Immunology Today 12(11): 386-388 (1991).
MHC class II molecules are expressed on a more limited set of antigen presenting cells, exemplified by B-cells, T-cells themselves, macrophages, and dendritic cells. These molecules present peptides in a way which is similar to class I molecules, except that the peptide is generally derived from an exogenous protein from the intercellular environment (e.g., bacteria). Class II molecules present their captured peptide to helper T cells expressing the CD4 co-receptor molecule and their activation generally results in the secretion of cytokines.
Thus, specific T cell immunity is controlled by two selective and independent binding events: first, binding of the peptide fragments of the antigens by the MHC class molecules, and second, binding of the resulting complexes by the clonotypic antigen receptors of the T cell. See, in this regard, Ada, Immunology and Cell Biology 72:447-454 (1994).
Tumor antigens are characteristic of tumor tissue and thus may be considered tissue specific. Tumor antigens result from alterations that frequently occur in malignant transformation of normal tissue. The alteration may be quantitative in that a particular normal antigen may decrease or increase in concentration. Such normal antigens that have increased concentration in tumors are generally referred to as “Tumor Associated Antigens (TAA).” Antigenic alteration may also be qualitative in that a new antigen, foreign to the host, may appear. These are termed “Tumor-Specific Antigens (TSA)” and may be present as new cell-surface structures or as new intracellular structures in the cytoplasm or nucleus.
Tumor specific antigens were first clearly demonstrated in mice that had been immunized with cells from a methylcholanthrene-induced sarcoma taken from syngeneic mice. These molecules were “recognized” by T cells in the recipient animal, and provoked a cytolytic T cell (“CTL” hereafter) response with lysis of the transplanted cells. The antigens expressed by the tumors and which elicited the T cell response were found to be different for each tumor. See Prehn, et al., J. Natl. Canc. Inst. 18: 769-778 (1957); Klein et al., Cancer Res. 20: 1561-1572 (1960); Gross, Cancer Res. 3: 326-333 (1943), Basombrio, Cancer Res. 30: 2458-2462 (1970) for general teachings on inducing tumors with chemical carcinogens and differences in cell surface antigens. This class of antigens has come to be known as “Tumor Specific Transplantation Antigens” or “TSTAs”. Following the observation of the presentation of such antigens when induced by chemical carcinogens, similar results were obtained when tumors were induced in vitro via ultraviolet radiation. See Kripke, J. Natl. Canc. Inst. 53: 333-1336 (1974) Prehn, R. T., and Main, J. M, Journal of Natl. Cancer Inst. 18:769 (1974).
While T cell mediated immune responses were observed for the types of tumor described supra, spontaneous tumors were thought to be generally non-immunogenic. These were therefore believed not to present antigens which provoked a response to the tumor in the tumor carrying subject. See Hewitt, et al., Brit. J. Cancer 33: 241-259 (1976).
The family of tum
−
antigen presenting cell lines are immunogenic variants obtained by mutagenesis of mouse tumor cells or cell lines, as described by Boon et al., J. Exp. Med. 152: 1184-1193 (1980), the disclosure of which is incorporated by reference. To elaborate, tum
−
antigens are obtained by mutating tumor cells which do not generate an immune response in syngeneic mice and will form tumors (i.e., “tum
+
” cells). When these tum
+
cells are mutagenized, they are rejected by syngeneic mice, and fail to form tumors (thus “tum
−
”). See Boon et al., Proc. Natl. Acad. Sci. USA 74: 272 (1977), the disclosure of which is incorporated by reference. Many tumor types have been shown to exhibit this phenomenon. See, e.g., Frost et al., Cancer Res. 43: 125 (1983).
It appears that tum
−
variants fail to form progressive tumors because they elicit an immune rejection process. The evidence in favor of this hypothesis includes the ability of “tum
−
” variants of tumors, i.e., those which do not normally form tumors, to do so in mice with immune systems suppressed by sublethal irradiation, Van Pel et al., Proc. Natl, Acad. Sci. USA 76: 5282-5285 (1979); and the observation that intraperitoneally injected tum
−
cells of mastocytoma P815 multiply exponentially for 12-15 days, and then are eliminated in only a few days in the midst of an influx of lymphocytes and macrophage (Uyttenhove et al., J. Exp. Med. 152: 1175-1183 (1980)). Further evidence includes the observation that mice acquire an immune memory which permits them to resist subsequent challenge to the same tum
−
variant, even when immunosuppressive amounts of radiation are administer
Ayyoub Maha
Gairin Jean Edouard
Mazarguil Honore
Monsarrat Bernard
van den Eynde Benoit
Chan Christina
DiBrino Marianne
Fulbright & Jaworski L.L.P.
Ludwig Institute for Cancer Research
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