Isolated nona-and decapeptides which bind to HLA molecules,...

Details Isolated nona-and decapeptides which bind to HLA molecules,... Isolated nona-and decapeptides which bind to HLA molecules,...

1998-06-18

2001-12-04

Chan, Christina Y. (Department: 1644)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

Method of regulating cell metabolism or physiology

C530S328000, C530S350000

Reexamination Certificate

active

06326200

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to peptides which are useful in the context of cellular immunology. More particularly, the invention relates to peptides which bind to HLA molecules on the surface of cells. At least some of these peptides also induce the activation of cytolytic T cells, when they are complexed with their partner HLA molecule. Also a part of the invention are the uses of these peptides in areas such as identifying HLA-A2 positive cells, provoking T cells, determining presence of particular T cells, as well as cytolytic T cells themselves.
BACKGROUND AND PRIOR ART
The study of the recognition or lack of recognition of cancer cells by a host organism has proceeded in many different directions. Understanding of the field presumes some understanding of both basic immunology and oncology.
Early research on mouse tumors revealed that these displayed molecules which led to rejection of tumor cells when transplanted into syngeneic animals. These molecules are “recognized” by T-cells in the recipient animal, and provoke a cytolytic T-cell response with lysis of the transplanted cells. This evidence was first obtained with tumors induced in vitro by chemical carcinogens, such as methylcholanthrene. 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).
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 initiate 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 macrophages (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 administered with the following challenge of cells (Boon et al.,
Proc. Natl. Acad. Sci. USA
74: 272-275 (1977); Van Pel et al., supra; Uyttenhove et al., supra). Later research found that when spontaneous tumors were subjected to mutagenesis, immunogenic variants were produced which did generate a response. Indeed, these variants were able to elicit an immune protective response against the original tumor. See Van Pel et al.,
J. Exp. Med.
157: 1992-2001 (1983). Thus, it has been shown that it is possible to elicit presentation of a so-called “tumor rejection antigen” in a tumor which is a target for a syngeneic rejection response. Similar results have been obtained when foreign genes have been transfected into spontaneous tumors. See Fearon et al.,
Cancer Res.
48: 2975-1980 (1988) in this regard.
A class of antigens has been recognized which are presented on the surface of tumor cells and are recognized by cytolytic T cells, leading to lysis. This class of antigens will be referred to as “tumor rejection antigens” or “TRAs” hereafter. TRAs may or may not elicit antibody responses. The extent to which these antigens have been studied, has been via cytolytic T cell characterization studies, in vitro, i.e., the study of the identification of the antigen by a particular cytolytic T cell (“CTL” hereafter) subset. The subset proliferates upon recognition of the presented tumor rejection antigen, and the cells presenting the tumor rejection antigens are lysed. Characterization studies have identified CTL clones which specifically lyse cells expressing the tumor rejection antigens. Examples of this work may be found in Levy et al.,
Adv. Cancer Res.
24: 1-59 (1977); Boon et al.,
J. Exp. Med.
152: 1184-1193 (1980); Brunner et al.,
J. Immunol.
124: 1627-1634 (1980); Maryanski et al.,
Eur. J. Immunol.
124: 1627-1634 (1980); Maryanski et al.,
Eur. J. Immunol.
12: 406-412 (1982); Palladino et al.,
Cancer. Res.
47: 5074-5079 (1987). This type of analysis is required for other types of antigens recognized by CTLs, including minor histocompatibility antigens, the male specific H-Y antigens, and the class of antigens referred to as “tum−” antigens, and discussed herein.
A tumor exemplary of the subject matter described supra is known as P815. See DePlaen et al.,
Proc. Natl. Acad. Sci. USA
85: 2274-2278 (1988); Szikora et al.,
EMBO J
9: 1041-1050 (1990), and Sibille et al.,
J. Exp. Med.
172: 35-45 (1990), the disclosures of which are incorporated by reference. The P815 tumor is a mastocytoma, induced in a DBA/2 mouse with methylcholanthrene and cultured as both an in vitro tumor and a cell line. The P815 line has generated many tum
−
variants following mutagenesis, including variants referred to as P91A (DePlaen, supra), 35B (Szikora, supra), and P198 (Sibille, supra). In contrast to tumor rejection antigens—and this is a key distinction—the tum
−
antigens are only present after the tumor cells are mutagenized. Tumor rejection antigens are present on cells of a given tumor without mutagenesis. Hence, with reference to the literature, a cell line can be tum
+
, such as the line referred to as “P1,” and can be provoked to produce tum
−
variants. Since the tum
−
phenotype differs from that of the parent cell line, one expects a difference in the DNA of tum
−
cell lines as compared to their tum
+
parental lines, and this difference can be exploited to locate the gene of interest in tum
−
cells. As a result, it was found that genes of turn variants such as P91A, 35B and P198 differ from their normal alleles by point mutations in the coding regions of the gene. See Szikora and Sibille, supra, and Lurquin et al.,
Cell
58: 293-303 (1989). This has proved not to be the case with the TRAs of this invention. These papers also demonstrated that peptides derived from the tum
−
antigen are presented by H-2
d
Class I molecules for recognition by CTLs. P91A is presented by L
d
, P35 by D
d
and P198 by K
d
.
PCT application PCT/U

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