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Compositions and methods for elimination of unwanted cells

This application claims benefit of PCT/GB98/00710, filed Mar. 10, 1998, which claims benefit of U.S. Ser. No. 60/045,164, filed Apr. 30, 1997 and UK 9705007.4, filed Mar. 11, 1997.

This invention relates to genes encoding fusogenic viral membrane glycoproteins and cells expressing such genes.

Prior art methods of treating cell proliferative disorders such as cancer have involved introduction into a patient of genes or vehicles containing genes encoding, for example, proteins that enhance the immunogenicity of tumor cells. These include pro-inflammatory cytokines, T cell co-stimulators and foreign MHC proteins which produce a local bystander effect due to local inflammatory response. The local inflammatory response is said to create a cytokine-rich environment which favors the generation of a systemic bystander effect by recruitment and activation of tumor-specific T cells.

Alternatively, it has been suggested to deliver to a tumor genes encoding enzymes that render tumor cells susceptible to a “pro-drug”. For thymidine kinase gene transfer, there is some evidence for a local bystander effect due to transfer of ganciclovir triphosphate (the activated drug) through tight junctions to adjacent tumor cells. However, many tumors lack the requisite tight junctions and the observed local and systemic bystander effects are therefore presumed to arise because of a local inflammatory response to cells that are killed by the pro-drug with associated activation of tumor-reactive T cells.

Replicating viruses have been used extensively as oncolytic agents for experimental cancer therapy (Russell, 1994, Semin. Cancer Biol. 5, 437-443). For example, a tissue culture suspension of mumps virus was used to treat 90 patients with terminal malignancies by local application to the tumor surface, by intratumoral, oral, rectal or intravenous inoculation, or by inhalation (Asada, 1974, Cancer, 34, 1907-1928). Toxicity was minimal and in 37 of the 90 patients the tumor disappeared or decreased to less than half of its initial size. Minor responses were observed in a further 42 patients. Tumor destruction was maximal several days after virus administration and was often followed by long-term suppression of tumor growth, perhaps due to stimulation of antitumor immunity.

Other viruses that have been used for cancer therapy in human subjects or experimental mouse models include West Nile virus, herpes simplex virus, Russian Far East encephalitis, Newcastle disease virus, Venezuelan equine encephalomyelitis, rabies, vaccinia and varicella (Russell, 1994, Eur. J. Cancer, 30A, 1165-1171). The rationale for these studies has been that many viruses replicate and spread more rapidly in neoplastic tissues than in nontransformed tissues and might therefore be expected to cause more damage to the tumor than to the host.

It is an object of the invention to provide compositions and methods for selective elimination of unwanted cells.

Another object of the invention is to selectively eliminate target cells by achieving a bystander effect.

Another object of the invention is to selectively induce syncytium formation of target cells, thereby eliminating the target cells.

The invention encompasses compositions comprising pharmaceutical formulations comprising a recombinant nucleic acid vector comprising a nucleotide sequence encoding a syncytium-inducing polypeptide expressible on a eukaryotic cell surface in admixture with a pharmaceutically acceptable carrier.

The invention also encompasses compositions comprising pharmaceutical formulations comprising a eukaryotic host cell containing a recombinant nucleic acid vector comprising a nucleotide sequence encoding a syncytium-inducing polypeptide and expressing the polypeptide on its surface, in admixture with a pharmaceutically acceptable carrier.

Preferably, in a composition according to the invention the sequence encodes at least a fusogenic portion of a viral fusogenic membrane glycoprotein.

Preferably, the sequence encodes a non-naturally occurring polypeptide. “Non-naturally occurring polypeptide refers to a recombinant polypeptide; for example, a chimeric polypeptide.

Preferably, the sequence encodes a fusogenic membrane glycoprotein having an artificially introduced protease-cleavage site.

Preferably, the sequence encodes a fusogenic membrane glycoprotein having an altered binding specificity.

Preferably, the sequence encodes a fusogenic membrane glycoprotein having enhanced fusogenicity, for example, as results from truncation of the carboxy terminal portion of a fusogenic membrane glycoprotein.

The eukaryotic host cell may be a human cell, such as a host cell selected from the group consisting of: neoplastic cells, migratory cells, T lymohocytes, B lymphocytes or other haemopoietic cells.