Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1996-10-18
2002-02-05
McKelvey, Terry (Department: 1636)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S456000
Reexamination Certificate
active
06344445
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to viral vectors and methods for their use, especially for example for transducing cells, for example malignant cells of hemopoietic lineage, and for inducing the expression of foreign genetic material in such cells. The invention also relates to pharmaceutical compositions based on such viral vectors, to the production of cells infected with such viral vectors, to pharmaceutical preparations based on such cells, and to their use for administration to humans and to non-human animals in order to achieve expression of foreign genetic material in vivo. Methods according to the invention can be used for example in cancer immunotherapy.
BACKGROUND OF THE INVENTION
Recombinant viral vectors are among several known agents available for the introduction of foreign genes into cells so that they can be expressed as protein. A central element is the target gene itself under the control of a suitable promoter sequence that can function in the cell to be transduced. Known techniques include non-viral methods, such as simple addition of the target gene construct as free DNA; incubation with complexes of target DNA and specific proteins designed for uptake of the DNA into the target cell; and incubation with target DNA encapsulated for example in liposomes or other lipid-based transfection agents.
A further option is the use of recombinant virus vectors engineered to contain the required target gene, and able to infect the target cells and hence carry into the cell the target gene in a form that can be expressed. A number of different viruses has been used for this purpose including retroviruses, adenoviruses, and adeno-associated viruses.
Specification EP 0 176 170 (Institut Merieux: B Roizman) describes foreign genes inserted into a herpes simplex viral genome under the control of promoter-regulatory regions of the genome, thus providing a vector for the expression of the foreign gene. DNA constructs, plasmid vectors containing the constructs useful for expression of the foreign gene, recombinant viruses produced with the vector, and associated methods are disclosed.
Specification EP 0 448 650 (General Hospital Corporation: Al Geller, XO Breakefield) describes herpes simplex virus type 1 expression vectors capable of infecting and being propagated in a non-mitotic cell, and for use in treatment of neurological diseases, and to produce animal and in vitro models of such diseases.
Recombinant viruses are known in particular for use in (e.g. corrective) gene therapy applied to gene deficiency conditions.
Examples of genes used or proposed to be used in corrective gene therapy include: the gene for human adenosine deaminase (ADA), as mentioned in for example WO 92/10564 (KW Culver et al: US Secretary for Commerce & Cellco Inc), and WO 89/12109 & EP 0 420 911 (IH Pastan et al); the cystic fibrosis gene and variants described in WO 91/02796 (L-C Tsui et al: HSC Research & University of Michigan), in WO 92/05273 (F S Collins & J M Wilson: University of Michigan) and in WO 94/12649 (RJ Gregory et al: Genzyme Corp).
The prior art of malignant tumor treatment includes studies that have highlighted the potential for therapeutic vaccination against tumors using autologous material derived from a patient's own tumor. The general theory behind this approach is that tumor cells may express one or more proteins or other biological macromolecules that are distinct from normal healthy cells, and which might therefore be used to target an immune response to recognise and destroy the tumor cells.
These tumor targets may be present ubiquitously in tumors of a certain type. A good example of this in cervical cancer, where the great majority of tumors express the human papillomavirus E6 and E7 proteins. In this case the tumor target is not a self protein, and hence its potential as a unique tumor-specific marker for cancer immunotherapy is clear.
There is increasing evidence that certain self proteins can also be used as tumor target antigens. This is based on the observation that they are expressed consistently in tumor cells, but not in normal healthy cells. Examples of these include the MAGE family of proteins. It is expected that more self proteins useful as tumor targets remain to be identified.
Tumor associated antigens and their role in the immunobiology of certain cancers are discussed for example by P van der Bruggen et al, in Current Opinion in Immunology, 4(5) (1992) 608-612. Other such antigens, of the MAGE series, are identified in T. Boon, Adv Cancer Res 58 (1992) pp 177-210, and MZ2-E and other related tumor antigens are identified in P. van der Bruggen et al, Science 254 (1991) 1643-1647; tumor-associated mucins are mentioned in PO Livingston, in current Opinion in Immunology 4 (5) (1992) pp 624-629; e.g. MUC1 as mentioned in J Burchell et al, Int J Cancer 44 (1989) pp 691-696.
Although some potentially useful tumor-specific markers have thus been identified and characterised, the search for new and perhaps more specific markers is laborious and time-consuming.
An experimental intracranial murine melanoma has been described as treated with a neuroattenuated HSV1 mutant 1716 (BP Randazzo et al, Virology 211 (1995) pp 94-101), where the replication of the mutant appeared to be restricted to tumor cells and not to occur on surrounding brain tissue.
Administration to mammals of cytokines as such (i.e. as protein) has been tried, but is often poorly tolerated by the host and is frequently associated with a number of side-effects including nausea, bone pain and fever. (A Mire-Sluis, TIBTech vol. 11 (1993); MS Moore, in Ann Rev Immunol 9 (1991) 159-91). These problems are exacerbated by the dose levels often required to maintain effective plasma concentrations.
It is known to modify live virus vectors to contain genes encoding a cytokine or a tumor antigen. Virus vectors have been proposed for use in cancer immunotherapy to provide a means for enhancing tumor immunoresponsiveness. Specification WO 86/07610 (Transgene: MP Kieny et al) discloses expression of human IL-2 in mammalian cells by means of a recombinant poxvirus comprising all or part of a DNA sequence coding for a human IL-2 protein. Specification EP 0 259 212 (Transgene SA: R Lathe et al) discloses viral vectors of the pox, adeno or herpes types, for controlling tumors, containing a heterologous DNA sequence coding for at least the essential regions of a tumor-specific protein. Specification WO 88/00971 (CSIRO, Australian National University: Ramshaw et al) discloses recombinant vaccine comprising a pox, herpes or adeno virus vaccine vector, especially vaccinia, including a nucleotide sequence expressing at least part of an antigenic polypeptide and a second sequence expressing at least part of a lymphokine (interleukin 1, 2, 3 or 4, or gamma interferon) which increases immune response to the antigenic polypeptide; and specification WO 94/16716 (E Paoletti et al: Virogenetics Corp.) describes attenuated recombinant vaccinia viruses containing DNA coding for a cytokine or a tumor antigen, e.g. for use in cancer therapy.
It has been proposed to use GMCSF-transduced tumor cells as a therapeutic vaccine against renal cancer. The protocols for corresponding trials involve removal of tumor material from the patients, and then transduction with the appropriate immunomodulator gene. The engineered cells are then to be re-introduced into the patient to stimulate a beneficial immune response.
Vectors based on herpesvirus saimiri, a virus of non-human primates, have been described as leading to gene expression in human lymphoid cells (B Fleckenstein & R Grassmann, Gene 102(2) (1991), pp 265-9). However, it has been considered undesirable to use such vectors in a clinical setting.
Although it is therefore known to introduce immunomodulatory and other genes into cells such as certain kinds of tumor cells, existing methods of achieving this are considered by the present inventors to have limitations, whether the difficulties are due to low quantitative amounts of transduction, to complexity, or to undesir
Boursnell Michael Edward Griffith
Brenner Malcolm Keith
Dilloo Dagmar
Inglis Stephen Charles
Cantab Pharmaceutical Research Limited
Klarquist & Sparkman, LLP
McKelvey Terry
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