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US-12617838-B2 - Auto/allo-immune defense receptors for the selective targeting of activated pathogenic T cells and NK cells

US12617838B2US 12617838 B2US12617838 B2US 12617838B2US-12617838-B2

Abstract

Embodiments of the disclosure concern engineered auto/allo-immune defense receptor (ADR)-expressing T cells that selectively target activated T cells, including pathogenic T cells, to incapacitate them. The chimeric receptors comprise moieties for targeting 4-1BB, 0X40, and CD40L, for example, whose expression is indicative of activated T cells. In particular embodiments, there are methods of preventing or treating conditions associated with activated T cells using adoptive T-cell transfer of cells encoding the ADRs.

Inventors

  • Maksim Mamonkin
  • Malcolm K. Brenner
  • FEIYAN MO

Assignees

  • BAYLOR COLLEGE OF MEDICINE

Dates

Publication Date
20260505
Application Date
20190425

Claims (20)

  1. 1 . A polypeptide, comprising: (1) an extracellular domain comprising one or more of an OX40-specific ligand, a 4-1BB-specific ligand, and CD40; that is operably linked to (2) an intracellular signaling domain promoting T-cell activation; wherein: (i) the polypeptide is encoded by a polynucleotide; (ii) the polypeptide comprises both (1) and (2); and (iii) the polypeptide comprises a transmembrane domain between (1) and (2).
  2. 2 . The polypeptide of claim 1 , wherein: (i) the intracellular signaling domain promoting T-cell activation is, from CD3 zeta subunit, DAP12, an Fc receptor, or a combination thereof; and/or (ii) the polypeptide further comprises 1, 2, or more costimulatory domains.
  3. 3 . The polypeptide of claim 1 , wherein: (i) the polypeptide comprises the OX40-specific ligand; or (ii) the polypeptide comprises the 4-1BB-specific ligand.
  4. 4 . The polypeptide of claim 3 , wherein: (i) the OX40-specific ligand is OX40L, an antibody that targets OX40, an OX40L-Fc fusion, or a combination thereof, or (ii) the 4-1BB-specific ligand is 4-1BBL, an antibody that targets 4-1BB, a 4-1BBL-Fc fusion, or a combination thereof.
  5. 5 . The polypeptide of claim 1 , wherein the polypeptide further comprises 1, 2, or more costimulatory domains.
  6. 6 . The polypeptide of claim 1 , wherein the polynucleotide further comprises sequence that encodes a spacer between (1) and (2).
  7. 7 . The polypeptide of claim 6 , wherein: (i) the spacer is between 10 and 220 amino acids in length; (ii) the spacer has sequence that facilitates surface detection with an antibody; (iii) the spacer is detectable with an anti-Fc Ab; and/or (iv) the spacer comprises IgG Fc portion.
  8. 8 . The polypeptide of claim 1 , wherein the polynucleotide further comprises a sequence encoding a chimeric antigen receptor, a T-cell receptor, or both.
  9. 9 . The polypeptide of claim 8 , wherein the chimeric antigen receptor comprises one or more costimulatory domains.
  10. 10 . The polypeptide of claim 1 , wherein the polynucleotide: (i) is present on a vector; or (ii) is present in a cell.
  11. 11 . The polypeptide of claim 10 , wherein the vector is a retroviral vector, lentiviral vector, adenoviral vector, or adeno-associated viral vector.
  12. 12 . The polypeptide of claim 10 , wherein the cell is: (i) a eukaryotic cell or a bacterial cell; or (ii) an immune cell.
  13. 13 . The polypeptide of claim 12 , wherein the immune cell is a T cell.
  14. 14 . The polypeptide of claim 13 , wherein the T cell comprises: (i) one or more chimeric antigen receptors; or (ii) one or more engineered T cell receptors (TCRs).
  15. 15 . The polypeptide of claim 8 , wherein the chimeric antigen receptor comprises 1, 2, or more costimulatory domains.
  16. 16 . The polypeptide of claim 1 , wherein the polynucleotide is comprised in an engineered cell.
  17. 17 . The polypeptide of claim 16 , wherein the engineered cell is an immune cell.
  18. 18 . The polypeptide of claim 17 , wherein the immune cell is a T cell.
  19. 19 . The polypeptide of claim 18 , wherein the T cell is a CAR-transduced T cell.
  20. 20 . The polypeptide of claim 18 , wherein the T cell is a T cell receptor (TCR)-transduced T cell.

Description

This application is a national phase application under 35 U.S.C. § 371 that claims priority to International Application No. PCT/US2019/029163 filed Apr. 25, 2019, which claims priority to U.S. Provisional Patent Application 62/662,817, filed Apr. 26, 2018, both of which are incorporated by reference herein in their entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under P50 CA126752 awarded by National Institutes of Health and the National Cancer Institute. The government has certain rights in the invention. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 21, 2020, is named Sequence_Listing.txt and is 18,752 bytes in size. TECHNICAL FIELD Embodiments of the disclosure include at least the fields of immunology, cell biology, molecular biology, and medicine. BACKGROUND Unwanted activation of T- and NK-cells often promotes life-threatening allo-immune reactions in patients receiving transplants or third party-derived therapeutic cells, leading to rejection of a transplanted organ/tissue or development of graft-versus-host disease (GvHD). Likewise, unwanted activation of autoreactive T-cells can lead to devastating autoimmune conditions, such as diabetes mellitus, autoimmune colitis, and multiple sclerosis. Currently, most of these diseases are not curable because of the inability to selectively eliminate pathogenic T cells. Instead, the patients are often treated with immunosuppressive drugs that render them immunodeficient and therefore susceptible to infections and malignant transformations. The present disclosure provides solutions for a long felt need in the art of safe and effective tissue transplantation and adoptive cell transfer, including utilizing off-the-shelf cells, by enhancing their ability of the transferred cells to control pathogenic conditions because of unwanted activation of the immune system. BRIEF SUMMARY The present disclosure is directed to compositions and methods related to cells utilized for adoptive transfer to control pathogenic conditions due to immune activation. The composition and methods apply to autologous and allogeneic cells. Although some steps may be taken to reduce the reactivity of allogeneic cells in the recipient individual, such cells would still be targeted by the immune system of the recipient (primarily T- and NK-cells), which would recognize them as foreign leading to rejection and limiting therapeutic benefit. The present disclosure overcomes this problem by modifying adoptive therapy cells to target activated pathogenic T, NK-T, and NK cells to prevent or treat medical conditions associated with their presence. In particular embodiments, the compositions and methods utilize adoptive T-cell transfer with cells that express receptors that selectively target pathogenic T cells while sparing resting T cells. In specific embodiments, the adoptive T-cells for transfer are engineered to express chimeric molecules that target pathogenic T cells that express certain target molecules whose presence on T cells is indicative of pathogenic T cells. In particular embodiments the disclosure concerns auto/allo-immune defense receptors (ADRs) for the selective targeting of pathogenic T-cells. Particular embodiments of the disclosure include methods of protecting engineered allogeneic T cells from elimination in a host individual by providing to the individual cells armed with ADRs. Embodiments also include methods that avoid allo-immune reactions in individuals receiving tissue or organ transplants, for example. In particular embodiments, cells encompassed by the disclosure have been modified or can be modified to allow them to survive in a recipient, including an allogeneic recipient. In specific cases, cells for adoptive cell therapy (including T cells, NKT cells, and so forth) are suitable for being utilized “Off-the-shelf”, which herein refers to cells kept in a repository, or bank, that may be provided (with or without further modification) to an individual in need thereof for a specific purpose. The individual in many cases is not the individual from which the cells were originally derived. The cells utilized in such a manner may be pre-manufactured to express an ADR, although in some cases the cells are obtained from a bank and afterwards are modified to express an ADR. The banked cells may or may not also express a CAR or recombinant TCR, or the cells obtained from the bank may afterwards be modified to express a CAR or recombinant TCR. Such practices allow for ease of use of third party-derived therapeutic cells without immune rejection by a host and without having to manufacture a patient-specific produce every time one is needed. In particular embodiments, there is an isolated polynucleotide, comprising sequence encoding: (1) one o