Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1998-08-07
2004-10-19
Ewoldt, G. R. (Department: 1644)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093210, C435S372300
Reexamination Certificate
active
06805861
ABSTRACT:
The present invention relates to immunotherapy, particularly to immunotherapy using cytotoxic T lymphocytes (CTL), and more particularly to adoptive immunotherapy.
There is evidence that anti-tumour CTL and anti-virus CTL play an important role in vivo. Tumour-reactive CTL have been shown to mediate tumour regression in animal models (1) and in man (2). Similarly, recent studies suggest that HIV-specific CTL may limit HIV virus load in vivo (3).
There is much interest in using in vitro generated CTL for adoptive immunotherapy of cancer. The potential importance of in vitro generated CTL is suggested in experiments with adenovirus transformed murine tumour cells (1). Nude mice were injected with tumour cells and large tumours were allowed to form. Tumour regression was observed when these mice were treated with CTL specific for the transforming E1A protein expressed in the tumour cells. Similarly, when in vitro generated CTL specific for gp100 were given to a melanoma patient tumour regression was observed (2). Thus, it is believed that adoptive transfer of T lymphocytes with defined specificity represents a promising therapy for cancer patients. Similarly, adoptively transferred CTL specific for cytomegalovirus seem to suppress CMV infection in patients who underwent bone marrow transplantation (4).
WO 93/17095 describes a method of producing, loading and using MHC class I molecules to specifically activate CTL derived from a patient in vitro and then returning the patient's activated CTL in a form of treatment. WO 93/17095 specifically teaches that it is the patients own CTL that should be used to treat the patient.
Chung et al (1994)
Proc. Natl. Acad. Sci. USA
91, 12654-12658 describes the production of functional three-domain single-chain T-cell receptors.
Moritz et al (1994)
Proc. Natl. Acad. Sci. USA
91, 4318-4322 describes CTL with a grafted recognition specificity for ERBB2-expressing tumour cells.
Roberts et al (1994)
Blood
84, 2878-2889 describes the targeting of HIV-infected cells by CD8
+
T lymphocytes armed with “universal” (chimaeric) T-cell receptors.
U.S. Pat. No. 5,359,046 describes “universal” (chimaeric) T-cell receptors.
Faber et al (1992)
J. Exp. Med.
176, 1283-1289 describes the generation of leukaemia-reactive CTL clones from genotypically HLA-identical bone marrow donor of a patient with leukaemia. In prior art allogeneic bone marrow transplantations the material comes directly from a healthy donor, and so is a mixed population and is not cloned.
A major rate limiting step of current adoptive immunotherapy is that it is patient-specific and dependent upon the isolation and in vitro expansion of specific CTL from the patient's own T lymphocyte pool. Thus, for each patient elaborate time-consuming and expensive in vitro work is required to generate sufficient numbers of specific CTL. Furthermore, in some patients the immune system may be severely suppressed, and it may be impossible to isolate specific CTL.
The present invention is aimed at overcoming these limitations and providing more efficient and potentially more effective adoptive immunotherapy with cytotoxic T lymphocytes (CTL) of patients, particularly cancer patients.
A first aspect of the invention provides a method of treating a patient with a disease wherein the patient contains diseased cells which cells contain, or are associated with, an abnormal molecule or an abnormally elevated amount of a molecule and which cells are capable of presenting at least part of said molecule on their surface by an HLA class I (or equivalent) molecule, the method comprising administering to the patient a therapeutically effective amount of cytotoxic T lymphocytes (CTL) which recognise at least part of said molecule when presented by an HLA class I (or equivalent) molecule on the surface of a cell characterised in that the cytotoxic T lymphocytes are not derived from the patient with a disease.
Thus the present invention overcomes the previous problems by, for example, generating CTL from, preferably, healthy individuals against selected peptides presented by the patient's HLA class I molecules. These CTL may be allo-restricted if the CTL donor does not express the class I molecule that presents the CTL recognised peptides, or they may be self MHC(HLA)-restricted if the CTL donor expresses the class I molecule that presents the CTL recognised peptides.
The CTL for administering to the patient are conveniently made using the method of the third aspect of the invention as described below.
By “HLA class I (or equivalent molecule)” we mean a HLA class I protein or any protein which is equivalent to a human HLA class I molecule from any other animal, particularly a vertebrate and especially a mammal. For example it is well known that in the mouse the MHC class I proteins are similar in structure to, and fulfill a similar role to, the human HLA class I proteins. Equivalent proteins to human HLA class I molecules can be readily identified in other mammalian species by a person skilled in the art, particularly using molecular biological methods.
By “at least part of said molecule” we include any fragment of said molecule that can be presented on the surface of a cell by an HLA class I (or equivalent) molecule.
By “an abnormally elevated amount of a molecule” we mean that in a diseased cell, compared to a normal cell, the molecule is present at >1.2 times the concentration; more preferably >2 times; still more preferably >5 times and most preferably >10 times the concentration. It will be clear that an abnormally elevated amount of a molecule includes the situation where normal (ie wild type) molecules are expressed in cell types where that molecule is not usually expressed (ie presence vs absence). Also, it will be clear that the abnormally elevated amount of a molecule may be due to abnormal activation of expression of a polypeptide which is not normally expressed in a cell or it may be due to an abnormal level of expression.
It is particularly preferred if the CTL administered to the patient is a clonal population of CTL.
It is also particularly preferred if the CTL (preferably a clonal population of CTL) administered to the patient are substantially free of other cell types.
The molecule may be any molecule at least part of which can be presented on the surface of a cell by an HLA class I (or equivalent) molecule.
Preferably, the molecule is a polypeptide including a carbohydrate-containing polypeptide such as a glycoprotein or is a carbohydrate including a peptide-containing carbohydrate, or is a lipid or glycolipid including a peptide-containing lipid or glycolipid.
As discussed in more detail below, abnormal molecules or an abnormally elevated amount of a molecule are associated with many diseases and diseased cells.
The method is particularly advantageous as it is effective in targeting self proteins (for example, those which are overexpressed in the diseased cell or are expressed in a disease cell whereas in a normal cell of the same type they are not expressed).
The patient may or may not be immuno-suppressed when receiving the CTL. It is preferred if the patient is immuno-suppressed.
It is more preferred if the said molecule is a polypeptide. It is well known in the art of immunology that peptide fragments derived from larger peptides or polypeptides are presented by HLA class I (or equivalent) molecules on the surface of a cell, especially diseased cells.
Although the CTL may be derived from the individual who is the patient from a sample taken before the patient acquired the disease, it is most preferred if the CTL are derived from an individual other than the patient.
Of course, it is preferred that the individual is a healthy individual. By “healthy individual” we mean that the individual is generally in good health, preferably has a competent immune system and, more preferably, is not suffering from any disease which can be readily tested for, and detected.
In a particularly preferred embodiment the CTL are derived from an individual which individual does not carr
Ewoldt G. R.
Imperial College Innovations Limited
Pabst Patent Group LLP
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