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EP-4735027-A1 - GENETICALLY ENGINEERED MUCOSAL-ASSOCIATED INVARIANT T (MAIT) CELLS FOR ADOPTIVE TRANSFER CELLTHERAPY

EP4735027A1EP 4735027 A1EP4735027 A1EP 4735027A1EP-4735027-A1

Abstract

The present disclosure relates in general to the field of genetic engineering of immune cells, specifically to mucosal-associated invariant T (MAIT) cells genetically engineered to express an exogeneous T cell receptor (TCR) and uses thereof. More specifically, the invention in embodiments thereof relates to cell compositions adapted for adoptive transfer cell therapy (ACT) providing for improved therapeutic modalities.

Inventors

  • MACHLENKIN, ARTHUR
  • LOTEM, MICHAL
  • SHAKED, Helena Lea
  • KLEIN SILBERMAN, Shira

Assignees

  • Pluri Biotech Ltd.
  • Hadasit Medical Research Services and Development Ltd.

Dates

Publication Date
20260506
Application Date
20240709

Claims (20)

  1. 1. A cell composition comprising a population of engineered mucosal-associated invariant T (MAIT) cells expressing an exogenous T cell receptor (TCR), wherein the MAIT cells are derived from placenta, optionally further comprising a pharmaceutically acceptable carrier.
  2. 2. The cell composition of claim 1, wherein the MAIT cells are derived from placental intervillous blood (IVB).
  3. 3. The cell composition of claim 1 or 2, which is adapted for adoptive transfer cell therapy (ACT).
  4. 4. The cell composition of any one of the preceding claims, which comprises 10 9 -10 n viable cells of said engineered MAIT cell population.
  5. 5. The cell composition of any one of the preceding claims, comprising at least 90% TCRVa7.2 + CD161 high cells.
  6. 6. The cell composition of any one of the preceding claims, wherein said TCR recognizes a tumor antigen.
  7. 7. The cell composition of claim 6, wherein the tumor antigen is selected from the group consisting of: NY-ESO-1, KRAS, p53, PIK3CA, PTEN, ERBB2 (HER2), AFP, KK-LC-1, RAC1-P29S, LAGE-1A, COL6A3, HA-2, HERV-E, BRAF, gplOO, alpha-fetoprotein, Desmoyokin/ AHNAKS2580F, Cancer/testis antigen 1, ERBB2H473Y, ERBB2IPE805G, minor H antigen (HA-1), PRAME, PSMA, TPBG, 5T4, MAGEA1, MAGE-A3/A6, MAGEA4/8, Melan-A/MART-1, NRAS and Wilms tumor 1 (WT-1).
  8. 8. The cell composition of claim 7, wherein said tumor antigen is selected from the group consisting of NY-ESO-1 and LAGE-1A.
  9. 9. The cell composition of any one of the preceding claims, wherein said TCR is capable of specific binding to an HLA-A2 -presented epitope.
  10. 10. The cell composition of claim 9, wherein said TCR comprises a TCR a chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of SEQ ID NO: 2, and a CDR3 having the amino acid sequence of SEQ ID NO: 3, and a TCR P chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 6.
  11. 11. The cell composition of claim 11, wherein said TCR comprises a TCR a chain having the amino acid sequence as set forth in SEQ ID NO: 7, optionally excluding the signal peptide at positions 1-20 thereof, and a TCR P chain having the amino acid sequence as set forth in SEQ ID NO: 8, optionally excluding the signal peptide at positions 1-21 thereof.
  12. 12. The cell composition of any one of the preceding claims, for use in therapy.
  13. 13. The cell composition for use of claim 12, wherein the use is in treating a subject having a tumor or malignancy.
  14. 14. The cell composition for use of claim 13, wherein the subject is afflicted with a tumor selected from the group consisting of: melanoma, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovary cancer, pancreatic cancer, prostate cancer, uterine cancer, cervical cancer, bladder cancer, stomach cancer, head and neck cancer, brain cancer, skin cancer and sarcoma.
  15. 15. The cell composition for use of claim 13 or 14, wherein the subject is afflicted with a treatment-resistant tumor or is not otherwise amenable for treatment with an immunotherapy comprising chimeric antigen receptor (CAR) T cells and/or therapeutic antibodies.
  16. 16. The cell composition for use of claim 15, wherein the use is in treating a subject afflicted with a condition associated with expression of an HLA class I-restricted antigen.
  17. 17. The cell composition for use of any one of claims 12-16, wherein said antigen is a low- density antigen characterized by surface expression of less than 50 antigen molecules per cell.
  18. 18. A cell composition adapted for adoptive transfer cell therapy (ACT), the composition comprising a substantially purified population of mucosal-associated invariant T (MAIT) cells engineered to express an exogenous T cell receptor (TCR), wherein the TCR recognizes a tumor antigen selected from the group consisting of NY-ESO-1 and LAGE- 1 A.
  19. 19. The cell composition of claim 18, wherein said TCR comprises a TCR a chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of SEQ ID NO: 2, and a CDR3 having the amino acid sequence of SEQ ID NO: 3, and a TCR P chain comprising a CDR1 having the amino acid sequence of SEQ ID NO: 4, a CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 6.
  20. 20. The cell composition of claim 19, wherein said TCR comprises a TCR a chain having the amino acid sequence as set forth in SEQ ID NO: 7, optionally excluding the signal peptide at positions 1-20 thereof, and a TCR P chain having the amino acid sequence as set forth in SEQ ID NO: 8, optionally excluding the signal peptide at positions 1-21 thereof.

Description

GENETICALLY ENGINEERED MUCOSAL-ASSOCIATED INVARIANT T (MAIT) CELLS FOR ADOPTIVE TRANSFER CELLTHERAPY FIELD OF THE INVENTION The present disclosure relates in general to the field of genetic engineering of immune cells. More specifically, the present disclosure provides mucosal-associated invariant T (MAIT) cells genetically engineered to express an exogeneous T cell receptor (TCR) and uses thereof. BACKGROUND OF THE INVENTION Mucosal-associated invariant T (MAIT) cells were first identified in humans, mice, and cattle as a population of aP T cells enriched in the double-negative (CD4 CD8 ) subset expressing an invariant Va7.2-Ja33 T cell receptor (TCR) in humans. The term MAIT was established due to the relative enrichment of these T cells within mucosal tissues. The restricting element of MAIT cells is the MHC-lb molecule MR1 (MHC -related 1), which presented intermediates in the vitamin B ((both riboflavin (vitamin B2) and folic acid (vitamin B9)) synthesis pathway to MAIT cells. Potent stimulatory ligands in the riboflavin synthesis pathway include 5-(2- oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) and 5-(2-oxoethylideneamino)-6-D- ribitylaminouracil (5-OE-RU) that are produced by a wide variety of bacteria, mycobacteria and yeasts during riboflavin synthesis. This pathway is absent from mammals; therefore, its immune detection allows effective host-pathogen discrimination. It has been found that MAIT cells can recognize cells infected by bacteria and produce IFN-y in response. It has been demonstrated that MAIT cells can protect mice from bacterial infection. Early phenotypic work established that human MAIT cells are CD8+ or double negative, have a primarily CCR7 effector memory phenotype, and express high levels of CD 161. Detailed phenotyping of MAIT cells also demonstrated that they share several characteristics with invariant natural killer T (iNKT) cells, including the expression of PLZF, a transcription factor that governs the innate-like functionality of iNKT cells. Expression of PLZF similarly imparts MAIT cells with innate-like functionality, as evidenced by the ability of cytokines to induce IFN-y production in the absence of TCR stimulation. Subsequent studies found that human MAIT cells do not express a single invariant TCR, but restricted TCRs comprising Va7.2-Ja33, Va7.2-Jal2, or Va7.2-Ja20, which are predominantly associated with a limited repertoire of the human 0 chains such as V02/V013. Thus, current understanding views MAIT cells as T cells that (a) express a semi-invariant Va7.2 -Ja33/12/20 TCR, (b) are activated by microbial vitamin B metabolite antigens presented by MR1 to execute both type 1 and type 17 effector functions, and (c) exhibit innate-like characteristics, governed by expression of PLZF, including the ability to be activated by cytokines independent of their TCR. MAIT cells contrast with conventional T cells which possess highly variable TCRs capable of targeting a vast array of peptide epitopes produced by viruses, bacteria and malignant cells. Conventional T cells therefore have exquisite specificity for individual peptides, and individual clones may undergo massive expansion to provide T cell memory. However, at the first encounter with a pathogen the frequency of any individual peptide-specific T cell will be very low. In contrast, the MAIT cell TCR provides an innate-like capacity to respond to a specific set of ligands without the need for expansion. Several properties of MAIT cells imply fundamental roles in mammalian immunity. First, MAIT cells have an intrinsic effector-memory phenotype, usually CD45RA CD45RO+CD95H1CD62LLOCD44H1, with capacity for rapid secretion of several pro -inflammatory cytokines. Second, MATT cells are remarkably abundant in human tissues, typically comprising 1-4% of all T cells in peripheral blood and up to 10% of airway T cells and 20-40% of liver T cells. Moreover, as each TCR recognizes the same ligand, early in an immune response, MAIT cells will markedly exceed the numbers of conventional antigen-specific T cells responding to cognate antigens. Recent studies using single-cell RNA sequencing technology and immunology techniques have revealed that MAIT cells demonstrate marked heterogeneity that recapitulates conventional T cell biology. It was demonstrated that this marked heterogeneity includes distinct CD4+ and CD8+ lineages, as well as “killer,” “helper,” and “regulatory” cell phenotypes -an indication that MAIT cells exercise complex functions. The conservation and abundance of MAIT cells is likely explained by their broad range of functionality attributable to different modes of activation, each triggering a distinct transcriptomic program. Because of their capability for diverse functional responses in diverse immunological contexts, these intriguing cells now appear to be multifunctional effectors central to the interface of innate and adaptive immunity. Already three major functions — antibacterial host defen