EP-4736887-A2 - CONJUGATED ANTIBODY OR BISPECIFIC TCELL ENGAGER WHICH SELECTIVELY BINDS EITHER TCR BETA CONSTANT REGION 1 (TRBC1) OR TRBC2

Abstract

The present invention relates to a chimeric antigen receptor (CAR) which comprises an antigen-binding domain which selectively binds TCR beta constant region 1 (TRBC1) or TRBC2; cells; such a T cells comprising such a CAR; and the use of such cells for the treatment of a T-cell lymphoma or leukaemia in a subject.

Inventors

• PULÉ, Martin
• MACIOCIA, Paul

Assignees

• Autolus Limited

Dates

Publication Date

20260506

Application Date

20150305

Claims (15)

1. An agent which selectively binds TCR beta constant region 1 (TRBC1) or TRBC2.
2. An agent according to claim 1, which selectively binds TRBC1.
3. An agent according to claim 1, which selectively binds TRBC2.
4. An agent according to any of claims 1 to 3 which is a conjugated antibody
5. An agent according to claim 4, which comprises a chemotherapeutic entity, optionally wherein the chemotherapeutic entity is a cytotoxic drug.
6. An agent according to any of claims 1 to 3, which is a bispecific T-cell engager []
7. An agent according to any preceding claim for use in treating a T-cell lymphoma or leukaemia in a subject.
8. An agent for use according to claim 7, wherein the agent causes selective depletion of the malignant T-cells, together with normal T-cells expressing the same TRBC as the malignant T-cells, but does not cause depletion of normal T-cells expressing the TRBC not expressed by the malignant T-cells.
9. An agent for use according to claim 7 and 8 which also comprises the step of investigating the TCR beta constant region (TCRB) of a malignant T cell from the subject to determine whether it expresses TRBC1 or TRBC2.
10. An agent according to claim 5 for use in a method for targeting the delivery of a chemotherapeutic entity to a cell which expresses either TRBC1 or TRBC2 in a subject.
11. A nucleic acid which encodes a bispecific T-cell engager according to claim 6.
12. A vector which comprises a nucleic acid according to claim 11.
13. A pharmaceutical composition which comprises an agent according to any of claims 1 to 6 and a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
14. An in vitro method for selecting a suitable therapy to treat a subject suffering from T-cell lymphoma or leukaemia which comprises: i) determining whether a malignant T cell from the subject expresses TRBC1 or TRBC2; and ii) selecting a therapy comprising an agent according to any of claims 1 to 6 based on the TRBC1 or TRBC2 expression of said malignant T cell.
15. An in vitro method for selecting a subject suffering from T-cell lymphoma or leukaemia to receive a therapy comprising an agent according to any of claims 1 to 6, which comprises: i) determining whether a malignant T cell from the subject expresses TRBC1 or TRBC2; and ii) selecting said subject to receive the therapy comprising an agent according to any of claims 1 to 6 based on the TRBC1 or TRBC2 expression of said malignant T cell.

Description

FIELD OF THE INVENTION The present invention relates to cells and agents useful in the treatment of T-cell lymphoma or leukaemia. BACKGROUND TO THE INVENTION Lymphoid malignancies can largely be divided into those which are derived from either T-cells or B-cells. T-cell malignancies are a clinically and biologically heterogeneous group of disorders, together comprising 10-20% of non-Hodgkin's lymphomas and 20% of acute leukaemias. The most commonly identified histological subtypes are peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS); angio-immunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL). Of all acute Lymphoblastic Leukaemias (ALL), some 20% are of a T-cell phenotype. These conditions typically behave aggressively, compared for instance with B-cell malignancies, with estimated 5-year survival of only 30%. In the case of T-cell lymphoma, they are associated with a high proportion of patients presenting with disseminated disease, unfavourable International Prognostic Indicator (IPI) score and prevalence of extra-nodal disease. Chemotherapy alone is not usually effective and less than 30% of patients are cured with current treatments. Further, unlike in B-cell malignancies, where immunotherapies such as the anti-CD20 monoclonal antibody rituximab have dramatically improved outcomes, there is currently no equivalently effective, minimally toxic immunotherapeutic available for the treatment of T-cell malignancies. An important difficulty in the development of immunotherapy for T-cell disorders is the considerable overlap in marker expression of clonal and normal T-cells, with no single antigen clearly able to identify clonal (malignant) cells. The same problem exists when targeting a pan-B-cell antigen to treat a B-cell malignancy. However, in this case, the concomitant depletion of the B-cell compartment results in relatively minor immunosuppression which is readily tolerated by most patients. Further, in therapies which result in particularly long-term depletion of the normal B-compartment, its loss can be largely abrogated by administration of pooled immunoglobulin. The situation is completely different when targeting T-cell malignancies. Here, concomitant depletion of the T-cell compartment leads to severe immunosuppression and severe toxicity. Further, there is no satisfactory way to mitigate loss of the T-cell compartment. The toxicity is in part illustrated by the clinical effects of the therapeutic monoclonal antibody Alemtuzumab. This agent lyses cells which express CD52 and has some efficacy in T-cell malignancies. The utility of this agent is greatly limited by a profound cellular immunodeficiency, largely due to T-cell depletion, with markedly elevated risk of infection. There is thus a need for a new method for targeted treatment of T-cell malignancies which is not associated with the above disadvantages. DESCRIPTION OF THE FIGURES Figure 1: A diagram of the αβ T-cell Receptor/CD3 Complex. The T-cell receptor is formed from 6 different protein chains which must assemble in the endoplasmic reticulum to be expressed on the cell surface. The four proteins of the CD3 complex (CD3ζ, CD3γ, CD3ε and CD3δ) sheath the T-cell Receptor (TCR). This TCR imbues the complex with specificity of a particular antigen and is composed of two chains: TCRα and TCRβ. Each TCR chain has a variable component distal to the membrane and a constant component proximal to the membrane. Nearly all T-cell lymphomas and many T-cell leukaemias express the TCR/CD3 complex.Figure 2: The segregation of T-cell Receptor β-constant region (TRBC)-1 and TRBC2 during T-cell receptor rearrangement. Each TCR beta chain is formed from genomic recombination of a particular beta variable (V), diversity (D), joining (J) and constant (TRBC) regions. The human genome contains two very similar and functionally equivalent TRBC loci known as TRBC1 and TRBC2. During TCR gene re-arrangement, a J-region recombines with either TRBC1 or TRBC2. This rearrangement is permanent. T-cells express many copies of a single TCR on their surface, hence each T-cell will express a TCR whose β-chain constant region is coded for by either TRBC1 or TRBC2.Figure 3: Alignment of human TRBC1 and TRBC2 at the amino acid level. The TCRβ constant chain coded for by TRBC1 and TRBC2 differ by only 4 amino acid differences: K / N at position 3 of the TRBC; N / K at position 4 of the TRBC; F / Y at position 36 of the TRBC; V / E at position 135 of the TRBC;Figure 4: Definitive demonstration that the JOVI-1 antibody binds to TRBC1 but not TRBC2. Genetic engineering of cells was used to definitively demonstrate that the JOVI-1 monoclonal antibody recognizes TRBC1 variant of the TCRβ constant chain. A tri-cistronic retroviral cassette was generated. This coded for both the TCRα and TCRβ chains of a human TCR which recognizes the minor histocompatibility antigen HA1, along with truncated human CD34 as a convenient marker gene. The HA1 TCR is