Cell

Abstract

The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising : (i) an antigen-binding domain; (ii) a spacer (iii) a trans-membrane domain; and (iv) an endodomain wherein the antigen binding domains of the first and second CARs bind to different antigens, and wherein each of the first and second CARs is an activating CAR comprising an activating endodomain.

Description

FIELD OF THE INVENTION[0001]The present invention relates to a cell which comprises more than one chimeric antigen receptor (CAR). The cell may be capable of specifically recognising a target cell, due to a differential pattern of expression (or non-expression) of two or more antigens by the target cell.BACKGROUND TO THE INVENTION[0002]A number of immunotherapeutic agents have been described for use in cancer treatment, including therapeutic monoclonal antibodies (mAbs), immunoconjugated mAbs, radioconjugated mAbs and bi-specific T-cell engagers.[0003]Typically these immunotherapeutic agents target a single antigen: for instance, Rituximab targets CD20; Myelotarg targets CD33; and Alemtuzumab targets CD52.[0004]However, it is relatively rare for the presence (or absence) of a single antigen effectively to describe a cancer.[0005]A particular problem in the field of oncology is provided by the Goldie-Coldman hypothesis: which describes that the sole targeting of a single antigen may ...

AI Technical Summary

Benefits of technology

[0142]By providing two or more CARs on the surface of the T cell, it is possible to target multiple cancer markers simultaneously, providing better therapeutic efficacy for heterogeneic tumours and avoiding the problem of cancer escape.

[0143]Because the CARs are expressed on the surface of the T cell as separate molecules, this approach overcomes the spatial and accessibility issues associated with TanCARs. T-cell activation efficiency is also improved. As each CAR has its own spacer, it is possible to tailor the spacer and therefore the distance that the binding domain projects from the T cell surface and its flexibility etc to the particular target antigen. This choice is unfettered by the design considerations associated with TanCARs, i.e. that one CAR needs to be juxta-posed to the T cell membrane and one CAR needs to be distal, positioned in tandem to the first CAR.

[0145]The two or more CARs will have portions of high homology, for example the transmembrane and / or intracellular signalling domains are likely to be highly homologous. If the same or similar linkers are use for the two CARs, then they will also be highly homologous. This would suggest that an approach where both CARs are provided on a single nucleic acid sequence would be inappropriate, because of the likelihood of homologous recombination between the sequences. However, the present inventors have found that by “codon wobbling” the portions of sequence encoding areas of high homology, it is possible to express two CARs from a single construct with high efficiency. Codon wobbling involves using alternative codons in regions of sequence encoding the same or similar amino acid sequences.FURTHER ASPECTS OF THE INVENTION

Problems solved by technology

A particular problem in the field of oncology is provided by the Goldie-Coldman hypothesis: which describes that the sole targeting of a single antigen may result in tumour escape by modulation of said antigen due to the high mutation rate inherent in most cancers.

This modulation of antigen expression may reduce the efficacy of known immunotherapeutics.

This heterogeneity of cancer cells introduces significant challenges in designing effective treatment strategies.

It has been observed that using a CAR approach for cancer treatment, tumour heterogeneity and immunoediting can cause escape from CAR treatment.

The problem with this approach is that the juxta-membrane scFv may be inaccessible due to the presence of the distal scFv, especially which it is bound to the antigen.

In view of the need to choose the relative positions of the two scFvs in view of the spatial arrangement of the antigen on the target cell, it may not be possible to use this approach for all scFv binding pairs.

Moreover, it is unlikely that the TanCar approach could be used for more than two scFvs, a TanCAR with three or more scFvs would be a very large molecule and the scFvs may well fold back on each other, obscuring the antigen-binding sites.

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