Polypeptide

Abstract

The present invention provides 5T4 tumour-associated antigen (TAA) for use in a method of immunotherapy of tumours. The invention also relates to a recombinant poxvirus vector from which at least one immune evasion gene has been deleted, which comprises a nucleic acid sequence encoding a 5T4 TAA and the use thereof in vaccinating against and in treating tumours.

Description

[0001] The present invention relates to a tumour-associated antigen (TAA) useful for eliciting an anti-tumour immunotherapeutic response in subjects. In particular, the invention relates to 5T4 antigen and its use in immunotherapy.BACKGROUND TO THE INVENTION[0002] A number of oncofoetal or tumour-associated antigens (TAAs) have been identified and characterised in human and animal tumours. In general, TAAs are antigens expressed during foetal development which are downregulated in adult cells, and are thus normally absent or present only at very low levels in adults. Tumour cells have been observed to resume expression of TAAs, and the application of TAAs for tumour diagnosis, targeting and immunotherapy has therefore been suggested.[0003] In particular, the recent cloning of tumour antigens recognised by T cells has caused considerable interest in the development of antigen specific cancer vaccines. However, many tumour associated antigens are non-mutated, poorly immunogenic tissue...

AI Technical Summary

Benefits of technology

The patent text describes the results of a study where mice were injected with a virus that expresses a tumour antigen called 5T4. The study found that the virus was safe and did not cause any harm to the mice. The mice also produced antibodies to the antigen. The study also found that the antigen is not present in important organs like the brain, liver, kidneys, and heart. This information is important for developing a safe and effective vaccine against 5T4.

Problems solved by technology

However, many tumour associated antigens are non-mutated, poorly immunogenic tissue differentiation antigens.

However, as indicated by results from clinical trials obtained to date, inducing therapeutic T cells to these antigens has proved extremely difficult.

The immune system is not able to differentiate the tumour antigen on a tumour cell from ordinary, self proteins.

A major barrier to the application of tumour immunotherapy approaches using non-mutated self cellular antigens is thus apparently the breaking of tolerance to such an antigen.

Thus, it could not be predicted whether 5T4 could prove to be an effective antigen for immunotherapy against cancer.

Although the use of poxvirus vectors is able to cause the antigens to be presented such that this tolerance may be overcome at least in part, the immunogenic effect observed with most poxvirus vectors is limited.

They encode so many antigenic proteins that antigenic variation is difficult, thus relying on active immune evasion to protect themselves from the mammalian immune system.

Preferably, the gene or gene product interferes with the working of the immune system, at least one level.

The E3L gene expresses a 25 Kd polypeptide which competes with P1 protein kinase for binding to dsRNA, an event which leads to activation of P1, phosphorylation of eIF2.alpha. and resultant failure of translation initiation complex assembly.

This pathway is ordinarily responsive to IFN activation, but is impeded by E3L expression thus allowing translation initiation to proceed unimpeded.

The B5R gene product thus may interfere with the alternative complement pathway.

However, in wild-type virus both of these genes are believed to be inactive due to fragmentation of the ORFs.

For example, a plasmid is cloned in E. Coli and then the same plasmid is transfected into yeast or mammalian cells even though it is not capable of replicating independently of the host cell chromosome.

The programs are not generally useful for motif-style searching.

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