Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1998-10-07
2002-04-02
Hauda, Karen M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093200, C435S325000, C435S320100, C514S04400A
Reexamination Certificate
active
06365151
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the field of cancer vaccination and immunotherapy.
BACKGROUND OF THE INVENTION
A current goal of cancer research is the identification of host factors that either predispose to tumor formation or serve to enhance tumor growth.
Genes that confer the ability to convert cells to a tumorigenic state are known as oncogenes. The transforming ability of a number of retroviruses has been localized in individual viral oncogenes (generally v-onc). Cellular oncogenes (generally c-onc) present in many species are related to viral oncogenes. It is generally believed that retroviral oncogenes may represent escaped and/or partially metamorphosed cellular genes that are incorporated into the genomes of transmissible, infectious agents, the retroviruses.
Some c-onc genes intrinsically lack oncogenic properties, but may be converted by mutation into oncogenes whose transforming activity reflects the acquisition of new properties, or loss of old properties. Amino acid substitution can convert a cellular proto-oncogene into an oncogene. For example, each of the members of the c-ras proto-oncogene family (H-ras, N-ras and K-ras) can give rise to a transforming oncogene by a single base mutation.
Other c-onc genes may be functionally indistinguishable from the corresponding v-onc, but are oncogenic because they are expressed in much greater amounts or in inappropriate cell types. These oncogenes are activated by events that change their expression, but which leave their coding sequence unaltered. The best characterized example of this type of proto-oncogene is c-myc. Changes in MYC protein sequence do not appear to be essential for oncogenicity. Overexpression or altered regulation is responsible for the oncogenic phenotype. Activation of c-myc appears to stem from insertion of a retroviral genome within or near the c-myc gene, or translocation to a new environment. A common feature in the translocated loci is an increase in the level of c-myc expression.
Gene amplification provides another mechanism by which oncogene expression may be increased. Many tumor cell lines have visible regions of chromosomal amplification. For example, a 20-fold c-myc amplification has been observed in certain human leukemia and lung carcinoma lines. The related oncogene N-myc is five to one thousand fold amplified in human neuroblastoma and retinoblastoma. In human acute myeloid leukemia and colon carcinoma lines, the proto-oncogene c-myb is amplified five to ten fold. While established cell lines are prone to amplify genes, the presence of known oncogenes in the amplified regions, and the consistent amplification of particular oncogenes in many independent tumors of the same type, strengthens the correlation between increased expression and tumor growth.
Immunity has been successfully induced against tumor formation by inoculation with DNA constructs containing v-onc genes, or by inoculation with v-onc proteins or peptides. A series of reports describe a form of “homologous” challenge in which an animal test subject is inoculated with either v-src oncoprotein or DNA constructs containing the v-src gene. Protective immunity was induced against tumor formation by subsequent challenge with v-src DNA or v-src-induced tumor cells. See, Kuzumaki et al.,
JNCI
(1988), 80:959-962; Wisner et al.,
J. Virol
. (1991), 65:7020-7024; Halpern et al.,
Virology
(1993), 197:480-484: Taylor et al.,
Virology
(1994), 205:569-573; Plachy et al.,
Immunogenetics
(1994), 40:257-265. A challenge is said to be “homologous” where reactivity to the product of a targeted gene is induced by immunization with the same gene, the corresponding gene product thereof, or fragment of the gene product. A challenge is “heterologous” where reactivity to the product of a targeted gene is induced by immunization with a different gene, gene product or fragment thereof.
WO 92/14756 (1992) describes synthetic peptides and oncoprotein fragments which are capable of eliciting T cellular immunity, for use in cancer vaccines. The peptides and fragments have a point mutation or translocation as compared to the corresponding fragment of the proto-oncogene. The aim is to induce immunoreactivity against the mutated proto-oncogene, not the wild-type proto-oncogene. WO 92/14756 thus relates to a form of homologous challenge.
EP 119,702 (1984) describes synthetic peptides having an amino acid sequence corresponding to a determinant of an oncoprotein encoded by an oncogenic virus, which determinant is vicinal to an active site of the oncoprotein. The active site is a region of the oncoprotein required for oncoprotein function, e.g., catalysis of phosphorylation. The peptides may be used to immunize hosts to elicit antibodies to the oncoprotein active site. EP 119,702 is thus directed to a form of homologous challenge.
The protein product encoded by a proto-oncogene constitutes a self antigen and, depending on the pattern of its endogenous expression, would be tolerogenic at the level of T cell recognition of the self peptides of this product. Thus, vaccination against cancers which derive from proto-oncogene overexpression is problematic.
Recent attempts have been made to induce immunity in vitro or in vivo to the product of the HER-2
eu proto-oncogene. The proto-oncogene encodes a 185-kDa transmembrane protein. The HER-2
eu proto-oncogene is overexpressed in certain cancers, most notably breast cancer. In each report discussed below, the immunogen selected to induce immunity comprised a purified peptide of the p185
HER-2
eu
protein, and not a cellular immunogen.
Disis et al.,
Cancer Res.
(1994) 54:16-20 identified several breast cancer patients with antibody immunity and CD4+helper/inducer T-cell immunity responses to p185
HER-2
eu
protein. Antibodies to p185
HER-2
eu
were identified in eleven of twenty premenopausal breast cancer patients. It was assumed prior to this work that patients would be immununologically tolerant to HER-2
eu as a self-protein and that immunity would be difficult to generate.
Disis et al.,
Cancer Res.
(1994) 54:1071-1076 constructed synthetic peptides identical to p185
HER-2
eu
protein segments with amino acid motifs similar to the published motif for HLA-A2.1-binding peptides. Out of four peptides synthesized, two were shown to elicit peptide-specific cytotoxic T-lymphocytes by primary in vitro immunization in a culture system using peripheral blood lymphocytes from a normal individual homozygous for HLA-A2. Thus, it was concluded that the p185
HER-2
eu
proto-oncogene protein contains immunogenic epitopes capable of generating human CD8+ cytotoxic T-lymphocytes.
The cytotoxic T cells elicited in the latter report were not, however, shown to recognize tumor cells, but only targets that bound the synthesized peptides. Other work (Dahl et al.,
J. Immunol.
(1996), 157:239-246) has demonstrated that cytotoxic cells may recognize targets that bind peptide but fail to recognize targets that endogenously synthesize peptide. It is thus unclear whether the cytotoxic cells elicited by Disis et al. would be capable of recognizing tumor cells. In any event, no protection against tumor growth was demonstrated by Disis et al.
Peoples et al.,
Proc. Natl. Acad. Sci. USA
(1995), 92:432-436, report the identification of antigenic peptides presented on the surface of ovarian and breast cancer cells by HLA class I molecules and recognized by tumor-specific cytotoxic T lymphocytes. Both HLA-A2-restricted breast and ovarian tumor-specific cytotoxic T lymphocytes recognized shared antigenic peptides. T cells sensitized against a nine-amino acid sequence of one of the peptides demonstrated significant recognition of HLA-A2 HER2
eu tumors.
It remains unclear whether Peoples et al. have successfully attacked proto-oncogene-encoded self, as the immunizing peptide which is expressed in the tumor cells contained an isoleucine at position
2
, whereas the peptide expressed in normal tissue contains valine residue at this position. Moreover, although stimulation of T cells occurred in vitro
England James M
Halpern Michael S
Beckerleg Anne-Marie S
Drinker Biddle & Keath LLP
Hauda Karen M.
Philadelphia Health and Educational Corporation
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