Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1998-05-13
2001-09-04
Crouch, Deborah (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C800S003000, C800S010000
Reexamination Certificate
active
06284239
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to murine models for the growth of patients' breast, ovarian and prostate cancers. The invention is more particularly related to immunodeficient mice containing surgical specimens of human primary breast, ovarian or prostate carcinomas implanted within, for instance, the gonadal fat pad. The present invention is also directed to methods for using such tumor-bearing mice, for example, to evaluate the effectiveness of treatments for breast, ovarian and/or prostate cancer or to identify carcinoma-associated antigens.
BACKGROUND OF THE INVENTION
Animal models for human carcinomas are valuable tools for the investigation and development of cancer therapies. However, several human carcinomas have proven exceptionally difficult to grow in animal models. For example, in spite of considerable effort, surgical specimens of human breast carcinomas have been resistant to growth in a variety of animal model systems, including the anterior chamber of the eye of guinea pigs, lethally irradiated or thymectomized mice, and nude and SCID mice. In nude mice, the incidence of tumor take is low even when the animals are supplemented with estrogen, and those tumors that do grow exhibit amplification of the HER-2
eu oncogene, which has been correlated with poor prognosis. Thus, the best of the present models are only effective for a limited category of extremely malignant carcinomas, and no acceptable animal models are presently available for the general experimental study of human breast cancer. The need for animal models is even greater for human prostate and ovarian cancers where, to date, less research has been conducted.
Accordingly, there is a need in the art for improved animal models for the study of human breast, ovarian and prostate cancers. The present invention fulfills these needs and further provides other related advantages.
SUMMARY OF THE INVENTION
Briefly stated, the present invention provides murine models for breast, ovarian and prostate carcinomas. In one aspect, an immunodeficient mouse containing human primary breast, ovarian or prostate carcinoma tissue is provided, wherein the carcinoma tissue is implanted within a gonadal fat pad of the immunodeficient mouse. In another aspect, an immunodeficient mouse is provided in which ovarian or prostate carcinoma tissue is implanted subcutaneously.
Within related aspects, the present invention provides methods for generating a murine model for breast, ovarian or prostate cancer. In one embodiment, the method comprises implanting a specimen of a human breast, ovarian or prostate carcinoma within the gonadal fat pad (or, alternatively, subcutaneously for ovarian or prostate carcinoma) of an immunodeficient mouse. In a preferred embodiment, the method further comprises removing at least a portion of the implanted carcinoma specimen and subsequently implanting the portion either within a gonadal fat pad of a second immunodeficient mouse or subcutaneously.
In yet another aspect, methods are provided for growing human breast, ovarian or prostate carcinoma tissue, comprising: (a) implanting a specimen of a human breast, ovarian or prostate carcinoma within a gonadal fat pad of an immunodeficient mouse, or, alternatively, implanting the specimen subcutaneously for ovarian or prostate carcinoma; and (b) allowing the carcinoma to grow within the immunodeficient mouse. In a preferred embodiment, such methods further comprise removing at least a portion of the implanted carcinoma specimen and subsequently implanting the portion either within a gonadal fat pad or subcutaneously in a second immunodeficient mouse.
In further aspects, the present invention provides methods for evaluating the effectiveness of a breast, ovarian or prostate cancer therapy, comprising: (a) implanting a specimen of a human breast, ovarian or prostate carcinoma within an immunodeficient mouse as described above; (b) exposing the immunodeficient mouse to a candidate therapy; and (c) determining a change in size of the implanted specimen, the extent of tumor cell death and/or the level of metastatic spread in the mouse, and therefrom determining the effectiveness of the therapy.
In another aspect, methods are provided for producing tumor-reactive human cytolytic T lymphocytes, comprising: (a) implanting a specimen of a human carcinoma containing human T lymphocytes within an immunodeficient mouse, as described above; (b) allowing the human T lymphocytes to grow within the immunodeficient mouse; (c) isolating a human cytolytic T lymphocyte from the specimen-bearing immunodeficient mouse; and (d) evaluating the lymphocyte for the ability to kill carcinoma cells, and therefrom identifying a tumor-reactive lymphocyte.
In a related aspect, methods are provided for generating an anti-tumor antiserum, comprising: (a) implanting a specimen of a human carcinoma containing human B cells within a gonadal fat pad of an immunodeficient mouse, wherein the carcinoma is a breast, ovarian or prostate carcinoma, or, alternatively, implanting the specimen subcutaneously for ovarian or prostate carcinoma; (b) allowing the human B cells to grow and produce human anti-tumor antibodies within the immunodeficient mouse; (c) isolating an antiserum from the immunodeficient mouse; and (d) evaluating the antiserum for the ability to bind to carcinoma cells, and therefrom identifying an anti-tumor antiserum.
In yet another related aspect, methods are provided for generating an anti-tumor monoclonal antibody, comprising: (a) implanting a specimen of a human carcinoma containing human B cells within an immunodeficient mouse, as described above; (b) allowing the human B cells to grow and produce human anti-tumor antibodies within the immunodeficient mouse; (c) generating a monoclonal antibody from the isolated B cells; and (d) evaluating the monoclonal antibody for the ability to bind to carcinoma cells, and therefrom identifying an anti-tumor monoclonal antibody.
Within other related aspects, the present invention provides tumor-reactive human cytolytic T lymphocytes, anti-tumor antisera, and monoclonal antibodies produced by the methods described above.
In a further aspect, methods are provided for isolating DNA molecules encoding tumor-specific antigens, such methods comprising: (a) implanting a specimen of a human carcinoma containing tumor-specific antigens within a gonadal fat pad of an immunodeficient mouse, wherein the carcinoma is a breast, ovarian or prostate carcinoma, or, alternatively, implanting the specimen subcutaneously for ovarian or prostate carcinoma; (b) allowing the carcinoma specimen to grow within the immunodeficient mouse; (c) obtaining sera from the immunodeficient mouse; and (d) isolating a DNA molecule encoding a tumor-specific antigen from the sera.
In yet another aspect, the present invention provides methods for treating cancer in a patient, wherein the cancer is a breast, ovarian or prostate cancer. In one embodiment, the method comprises administering to a patient a tumor-reactive cytolytic T lymphocyte as described above. In another embodiment, the method comprises administering to a patient an anti-tumor monoclonal antibody as described above.
These and other aspects of the present invention will become apparent upon reference to the following detailed description. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.
DETAILED DESCRIPTION OF THE INVENTION
As noted above, the present invention is generally directed to the generation of new animal models for human carcinomas. More specifically, in one embodiment the animal models described herein are prepared by implantation of primary malignant human breast, ovarian or prostate tissue into a gonadal fat pad of an immunodeficient mouse. In a second embodiment, the inventive animal models are prepared by subcutaneous implantation of primary malignant human ovarian or prostate tissue in an immunodeficient mouse. Such models may be used, for example, to grow human breast, ovarian or prostate
Bumpers Harvey L.
Sechrist Heather
Subjeck Elizabeth Repasky
Corixa Corporation
Crouch Deborah
Seed Intellectual Property Law Group PLLC
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