WO2017205254A1 - Cellules immunitaires exprimant un récepteur de lymphocytes t couplé à un anticorps (actr) à utiliser dans l'inhibition de cellules cancéreuses exprimant l'immunoglobuline de surface - Google Patents

Cellules immunitaires exprimant un récepteur de lymphocytes t couplé à un anticorps (actr) à utiliser dans l'inhibition de cellules cancéreuses exprimant l'immunoglobuline de surface Download PDF

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Publication number
WO2017205254A1
WO2017205254A1 PCT/US2017/033767 US2017033767W WO2017205254A1 WO 2017205254 A1 WO2017205254 A1 WO 2017205254A1 US 2017033767 W US2017033767 W US 2017033767W WO 2017205254 A1 WO2017205254 A1 WO 2017205254A1
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cells
cell
domain
receptor
subject
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PCT/US2017/033767
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English (en)
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Heather Huet
Seth Ettenberg
Michael Fray
Tooba CHEEMA
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Unum Therapeutics
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4632—T-cell receptors [TCR]; antibody T-cell receptor constructs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the mammalian adaptive immune system is characterized by the ability of B cells and T cells to sense and respond to the presence of an enormously wide variety of foreign material, called antigens. This ability to sense antigens the body has never before encountered is facilitated by special receptors on the surface of B and T cells.
  • BCR B Cell Receptor
  • binding of the BCR can lead to an activation and expansion of the B cells that can sense this antigen, leading to the mounting of an immune response to the invaders.
  • Antibodies are the soluble form of the BCRs that responded to the foreign antigen; and they target the invaders for neutralization or destruction.
  • Ig- ⁇ and Ig- ⁇ transmembrane proteins, Ig- ⁇ and Ig- ⁇ .
  • Ig- ⁇ and Ig- ⁇ have both hydrophobic surfaces that are exposed to the plasma membrane environment and hydrophilic surfaces that can interact with the immunoglobulin moiety of the BCRs. Williams et al., (1993), Mol. Immunol.
  • B cells can express the IgM and/or IgD isoform of the BCR.
  • B cells When B cells are activated, they frequently undergo class-switching, in which the Fc portion of their Ig portion is switched from the IgM or IgD isotype to the IgG, IgA, or IgE isotype.
  • FcRs FcR Receptors
  • Immune cells expressing Fc receptors can bind to the Fc portion of antibodies that are attached to target cells such as invading pathogens, leading to elimination of the target cells via, e.g., antibody-dependent cell-mediated cytotoxicity (ADCC).
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • FcR-expressing immune cells could interact with the Fc portion of membrane-bound Ig molecules such as BCRs and trigger the same effects (e.g., ADCC) to eliminate the cells expressing the membrane-bound Ig.
  • T cells expressing an IgD receptor facilitate activation of B cells expressing IgD, rather than eliminate such B cells.
  • the present disclosure is based on the unexpected discovery that immune cells such as T cells expressing a surface antibody-coupled T cell receptor (ACTR) successfully induced direct cytotoxicity of pathogenic cells such as cancer cells that express surface
  • ACTR surface antibody-coupled T cell receptor
  • one aspect of the present disclosure features a method for inhibiting pathogenic cell growth, the method comprising contacting pathogenic cells that express a surface immunoglobulin (Ig, such as IgG) with an effective amount of an immune cell that expresses a surface chimeric receptor (an ACTR), which comprises at least an Fc binding domain, and a cytoplasmic signaling domain, and optionally one or more of a transmembrane domain; a co-stimulatory signaling domain; and a hinge domain.
  • Ig surface immunoglobulin
  • an ACTR surface chimeric receptor
  • the contacting step may be performed by administering the T cell that expresses the chimeric receptor to a subject having pathogenic cells that express surface Ig molecules, such as IgG.
  • the pathogenic cells are cancer cells.
  • Such cancer cells may be of an epithelial origin, for example, breast carcinoma cells, colon carcinoma cells, liver carcinoma cells, and lung carcinoma cells.
  • the cancer cells may be of a B cell origin, for example, B-lineage acute lymphoblastic leukemia cells, B-cell chronic lymphocytic leukemia cells, B-cell non- Hodgkin’s lymphoma cells, Hairy cell leukemia cells, and multiple myeloma cells.
  • the subject may not be co-administered with a therapeutic Fc-containing agent for inhibiting the growth of the cancer cells.
  • the pathogenic cells expressing surface Ig may be pathogenic immune cells or cells infected with a pathogen such as a virus.
  • the immune cell may further express an exogenous polypeptide comprising a co-stimulatory domain or a ligand of a co-stimulatory factor, wherein the exogenous polypeptide facilitates the chimeric receptor to elicit a co- stimulatory signal.
  • a pharmaceutical composition comprising the ACTR-expressing immune cells for use in inhibiting any of the pathogenic cells described herein that express surface Ig molecules and/or for treating a disease or disorder associated with such pathogenic cells; and (ii) use of the ACTR-expressing immune cells in manufacturing a medicament for use in achieving the therapeutic purposes as described herein.
  • Figure 1 includes diagrams showing IgG expression on the surface of five multiple myeloma cell lines.
  • Panel A a chart showing surface IgG levels of cell lines U266B1, NCI-H929, KMS-20, LP-1, and EJM, as indicated by mean fluorescence intensity (MFI).
  • Panel B a table showing the Ig isotype and MFI values of the just-noted cell lines.
  • Panel C a chart showing the geometric mean fluorescence intensity (gMFI) of the anti-IgG fluorescent signal for each cell line and human B cell populations derived from donor PBMCs as indicated.
  • Panel D a table showing the MFI values of the listed cells.
  • Figure 2 includes charts showing Jurkat-ACTR T cell activation in the presence of some of the human myeloma cell lines.
  • Panel A Jurkat-ACTR T cells, which express surface ACTR.
  • Panel B Jurkat-Mock T cells, which do not express surface ACTR.
  • Figure 3 includes charts showing Jurkat-ACTR T cell activation in the presence of human myeloma cell lines and in the presence or absence of cell culture supernatant collected from 1E6 EJM, LP-1, or KMS-20 cells cultured for 72 hours.
  • Panel A a chart showing IgG levels in supernatant samples collected from 3-day cultures of cell lines U266, EJM, LP-1, and KMS-20. Error bars represent standard deviation (SD) of duplicate wells.
  • Panel B a chart showing activation of Jurkat-ACTR T cells in the presence or absence of target cells (EJM, LP-1, KMS-20, and H929) or in the presence of culture supernatants.
  • Figure 7 includes charts showing that ACTR-T cells, but not Mock T cells, induced cytotoxicity on IgG expressing multiple myeloma cell lines LP-1 (panel A), EJM (panel B), and KMS-20 (panel C).
  • Chimeric receptors or antibody-coupled T-cell receptor (ACTR), as used herein interchangeably, are non-naturally-occurring receptors comprising an Fc binding domain with binding affinity and specificity for an Fc fragment(“Fc binder”) and a cytoplasmic signaling domain.
  • the chimeric receptor may optionally further comprise a co- stimulatory domain, a transmembrane domain, and/or a hinge domain.
  • an Fc binder can be an antibody or an antigen- binding fragment thereof that specifically binds the Fc portion of an Ig such as a membrane-bound Ig.
  • Ig such as a membrane-bound Ig.
  • examples include, but are not limited to, a single-chain variable fragment (scFv), a domain antibody, or a nanobody.
  • an Fc binder can be a synthetic peptide that specifically binds the Fc portion, such as a Kunitz domain, a small modular immunopharmaceutical (SMIP), an adnectin, an avimer, an affibody, a DARPin, or an anticalin, which may be identified by screening a peptide combinatory library for binding activities to Fc.
  • SMIP small modular immunopharmaceutical
  • Fc-gamma receptors examples include, without limitation, CD64A, CD64B, CD64C, CD32A, CD32B, CD16A, and CD16B.
  • An example of an Fc-alpha receptor is Fc ⁇ R1/CD89.
  • Fc-epsilon receptors include, without limitation, Fc ⁇ RI and Fc ⁇ RII/CD23. Table 1 below lists exemplary Fc receptors for use in constructing the chimeric receptors described herein and their binding activity to corresponding Fc domains:
  • the Fc receptor used for constructing a chimeric receptor or ACTR as described herein may be a naturally-occurring polymorphism variant (e.g., the CD16 V158 polymorphism variant described herein). Some examples are provided in Table 2 below.
  • ligand binding domain of an Fc receptor for use in the chimeric receptors described herein will be apparent to one of skill in the art. For example, it may depend on factors such as the binding affinity of the Fc receptor to its ligand, for example, the Fc portion of a membrane-bound Ig.
  • the Fc binding domain of an ACTR described herein comprises an amino acid sequence that is at least 90% (e.g., 91, 92, 93, 94, 95, 96, 97, 98, 99%) identical to the amino acid sequence of the Fc binding domain of a naturally- occurring Fc-gamma receptor, an Fc-alpha receptor, or an Fc-epsilon receptor.
  • the “percent identity” of two amino acid sequences can be determined using the algorithm of Karlin and Altschul Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, modified as in Karlin and Altschul Proc. Natl. Acad. Sci. USA 90:5873-77, 1993. Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. J. Mol. Biol.215:403-10, 1990.
  • BLAST protein searches can be performed with the
  • one or more residues of the extracellular domain of an Fc receptor involved in direct interaction, or predicted to be in direct interaction, with a wild-type Fc fragment may be mutated, for example to enhance the direct interaction.
  • the chimeric receptors described herein may comprise at least one co-stimulatory signaling domain.
  • co-stimulatory signaling domain refers to at least a portion of a protein that mediates signal transduction within a cell to induce an immune response, such as an effector function.
  • the co-stimulatory signaling domain of the chimeric receptor described herein can be a cytoplasmic signaling domain from a co-stimulatory protein, which transduces a signal and modulates responses mediated by immune cells, such as T cells, NK cells, macrophages, neutrophils, or eosinophils.
  • co-stimulatory signaling domains for use in the chimeric receptors can be the cytoplasmic signaling domain of co-stimulatory proteins, including, without limitation, members of the B7/CD28 family (e.g., B7-1/CD80, B7-2/CD86, B7-H1/PD-L1, B7-H2, B7-H3, B7-H4, B7-H6, B7-H7, BTLA/CD272, CD28, CTLA-4, Gi24/VISTA/B7-H5, ICOS/CD278, PD- 1, PD-L2/B7-DC, and PDCD6); members of the TNF superfamily (e.g.,4- 1BB/TNFSF9/CD137, 4-1BB Ligand/TNFSF9, BAFF/BLyS/TNFSF13B, BAFF
  • DR3/TNFRSF25 GITR/TNFRSF18, GITR Ligand/TNFSF18, HVEM/TNFRSF14, LIGHT/TNFSF14, Lymphotoxin-alpha/TNF-beta, OX40/TNFRSF4, OX40
  • CD84/SLAMF5 CD229/SLAMF3, CRACC/SLAMF7, NTB-A/SLAMF6, and
  • the co- stimulatory signaling domain is of 4-1BB, CD28, OX40, ICOS, CD27, GITR, HVEM, TIM1, LFA1(CD11a) or CD2, or any variant thereof. In other embodiments, the co- stimulatory signaling domain is not derived from 4-1BB.
  • the mutations are substitution of a lysine at each of positions 186 and 187 with a glycine residue of the CD28 co- stimulatory domain, referred to as a CD28 LL ⁇ GG variant. Additional mutations that can be made in co-stimulatory signaling domains that may enhance or reduce co-stimulatory activity of the domain will be evident to one of ordinary skill in the art.
  • the co-stimulatory signaling domain is of 4-1BB, CD28, OX40, or
  • the ITIM motif comprises the amino acid sequence S/I/V/LxYxxI/V/L. Upon stimulation of an ITIM, the motif becomes phosphorylated and reduce activation of molecules involved in cell signaling, thereby transducing an inhibitory signal.
  • the cytoplasmic domain comprising an ITIM is of a Killer-cell
  • KIR immunoglobulin-like receptor
  • the cytoplasmic signaling domain comprising an ITAM is of CD3 ⁇ or Fc ⁇ R1 ⁇ .
  • the ITAM-containing cytoplasmic signaling domain is not derived from human CD3 ⁇ .
  • the ITAM- containing cytoplasmic signaling domain is not derived from an Fc receptor, when the extracellular ligand-binding domain of the same chimeric receptor construct is derived from CD16A.
  • the hinge domain is (Gly 4 Ser) 9 (SEQ ID NO: 61). In some embodiments, the hinge domain is (Gly 4 Ser) 12 (SEQ ID NO: 62). In some embodiments, the hinge domain is (Gly 4 Ser) 15 (SEQ ID NO: 63). In some embodiments, the hinge domain is (Gly 4 Ser) 30 (SEQ ID NO: 64). In some embodiments, the hinge domain is (Gly 4 Ser) 45 (SEQ ID NO: 65). In some embodiments, the hinge domain is (Gly 4 Ser) 60 (SEQ ID NO: 66).
  • the nucleic acid is RNA. II. Host Cells Expressing Chimeric receptors
  • the host cells are immune cells, such as T cells, NK cells, macrophages, neutrophils, eosinophils, or any combination thereof.
  • immune cells such as T cells, NK cells, macrophages, neutrophils, eosinophils, or any combination thereof.
  • the vectors for expression of the chimeric receptors are retroviruses.
  • the vectors for expression of the chimeric receptors are lentiviruses.
  • the vectors for expression of the chimeric receptors are gamma-retroviruses.
  • the vectors for expression of the chimeric receptors are adeno-associated viruses (AAVs).
  • PF-04605412 Pfizer/Xencor
  • hu14.18K322A Adalimumab, Ado-Trastuzumab emtansine, Alemtuzumab, Basiliximab, Bevacizumab, Belimumab, Brentuximab, Canakinumab, Cetuximab, Daclizumab, Daratumumab, Denosumab, Dinoutuzimab, Eculizumab, Efalizumab, Elotuzumab, Epratuzumab, Gemtuzumab, Golimumab, Infliximab, Ipilimumab, Labetuzumab,
  • the immune cells expressing the chimeric receptors described herein may be autologous to the subject, i.e., the immune cells are obtained from the subject in need of the treatment, genetically engineered for expression of the chimeric receptor constructs, and then administered to the same subject. Administration of autologous cells to a subject may result in reduced rejection of the host cells as compared to administration of non- autologous cells.
  • the host cells are allogeneic cells, i.e., the cells are obtained from a first subject, genetically engineered for expression of the chimeric receptor construct, and administered to a second subject that is different from the first subject but of the same species.
  • allogeneic immune cells may be derived from a human donor and administered to a human recipient who is different from the donor.
  • the subject is a human subjecting suffering from an infectious disease that results expression surface Ig.
  • the infectious disease is a viral infection or a bacterial infection.
  • infection of a cell with the infectious agent results in expression of surface Ig on the infected cell.
  • Pharmaceutically acceptable carriers including buffers, are well known in the art, and may comprise phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; amino acids; hydrophobic polymers; monosaccharides; disaccharides; and other carbohydrates; metal complexes; and/or non- ionic surfactants. See, e.g., Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K. E. Hoover. IV. Combination Treatments

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Abstract

L'invention concerne des méthodes d'utilisation de cellules immunitaires exprimant des récepteurs chimériques pour inhiber la croissance de cellules pathogènes (par exemple, des cellules cancéreuses ou des lymphocytes B pathogènes) qui expriment une immunoglobuline de surface.
PCT/US2017/033767 2016-05-23 2017-05-22 Cellules immunitaires exprimant un récepteur de lymphocytes t couplé à un anticorps (actr) à utiliser dans l'inhibition de cellules cancéreuses exprimant l'immunoglobuline de surface WO2017205254A1 (fr)

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US201662340175P 2016-05-23 2016-05-23
US62/340,175 2016-05-23

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WO2017205254A1 true WO2017205254A1 (fr) 2017-11-30

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016040441A1 (fr) * 2014-09-09 2016-03-17 Unum Therapeutics Récepteurs chimériques et utilisations de ceux-ci en thérapie immunitaire

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016040441A1 (fr) * 2014-09-09 2016-03-17 Unum Therapeutics Récepteurs chimériques et utilisations de ceux-ci en thérapie immunitaire

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KOCHENDERFER, JN ET AL.: "Construction and preclinical evaluation of an anti- CD 19 chimeric antigen receptor", JOURNAL OF IMMUNOTHERAPY, vol. 32, no. 7, 1 September 2009 (2009-09-01), pages 689 - 702, XP002667048, Retrieved from the Internet <URL:doi:10.1097/CJI.0b013e3181ac6138> *
VERA, J ET AL.: "T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells", BLOOD, vol. 108, no. 12, 1 December 2006 (2006-12-01), pages 3890 - 3897, XP055232575, Retrieved from the Internet <URL:doi:10.1182/blood-2006-04-017061> *

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