WO2022099175A1 - Immunothérapies ciblant cd33 - Google Patents
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Classifications
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- 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]
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- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
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- A61K39/4644—Cancer antigens
- A61K39/464402—Receptors, cell surface antigens or cell surface determinants
- A61K39/464411—Immunoglobulin superfamily
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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
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
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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
- C07K14/70514—CD4
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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
- C07K14/70521—CD28, CD152
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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
- C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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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
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/90—Isomerases (5.)
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- C12Y—ENZYMES
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
Definitions
- the present disclosure relates to improved adoptive cell therapies directed against CD33. More particularly, the disclosure relates to anti-CD33 VHH-containing chemically regulated signaling molecules, anti-CD33 VHH-containing chimeric antigen receptors, cells, and related methods of treatment using the same.
- Cancer The global burden of cancer doubled between 1975 and 2000. Cancer is the second leading cause of morbidity and mortality worldwide, with approximately 14.1 million new cases and 8.2 million cancer related deaths in 2012.
- the most common cancers are breast cancer, lung and bronchus cancer, prostate cancer, colon and rectum cancer, bladder cancer, melanoma of the skin, non-Hodgkin lymphoma, thyroid cancer, kidney and renal pelvis cancer, endometrial cancer, leukemia, and pancreatic cancer.
- the number of new cancer cases is projected to rise to 22 million within the next two decades.
- CAR T cell therapy has met with limited success due to poor CAR expression, in vivo expansion of CAR T cells, rapid disappearance of the cells after infusion, disappointing clinical activity, and antigen escape.
- the present disclosure generally relates, in part, to VHH-based dimerizing agent regulated immunoreceptor complexes (DARICs), polynucleotides encoding the same, compositions thereof, and methods of making and using the same to treat cancer.
- DARICs VHH-based dimerizing agent regulated immunoreceptor complexes
- a non-natural cell comprises: a first polypeptide comprising an FRB multimerization domain polypeptide or variant thereof, a CD8a transmembrane domain or a CD28 transmembrane domain, a CD 137 co-stimulatory domain, and/or a CD3( ⁇ primary signaling domain; and a second polypeptide comprising an VHH antibody that binds a target antigen, an FKBP multimerization domain polypeptide or variant thereof, a hinge domain selected from the group consisting of CD28, CD4, and IgG4 or a spacer domain selected from the group consisting of GGS and GGR, and a CD4 transmembrane domain or a CD28 transmembrane domain, and optionally one or more costimulatory domains selected from a co-stimulatory molecule selected from the group consisting of TNFR, CD28, MYD88, CD40, CD4, CD278 (ICOS), interleukin 2 receptor beta (IL2RP), signaling lympho
- a VHH DARIC binds full-length CD33.
- a VHH DARIC binds a CD33 splice variant.
- the CD33 splice variant lacks the 124 amino acids encoded by exon 2 of the human CD33 gene (CD33 C2 variant).
- the CD33 splice variant lacks 54 carboxyterminal amino acids due to an early translation stop signal residing in exon 7a.
- the CD33 splice variant lacks the 124 amino acids encoded by exon 2 and 54 carboxy-terminal amino acids due to an early translation stop signal residing in exon 7a.
- a VHH DARIC binds both full-length CD33 and a CD33 splice variant.
- a non-natural cell comprises: a first polypeptide comprising an FRB multimerization domain polypeptide or variant thereof, a CD8a transmembrane domain or a CD28 transmembrane domain, a CD 137 co-stimulatory domain, and/or a CD3( ⁇ primary signaling domain; and a second polypeptide comprising an anti-CD33 VHH antibody that has an amino acid sequence set forth in any one of SEQ ID NOs: 2-21, an FKBP multimerization domain polypeptide or variant thereof, a hinge domain selected from the group consisting of CD28, CD4, and IgG4 or a spacer domain selected from the group consisting of GGS and GGR, and a CD4 transmembrane domain or a CD28 transmembrane domain, and optionally one or more co-stimulatory domains selected from a co-stimulatory molecule selected from the group consisting of TNFR, CD28, MYD88, CD40, CD4, CD278 (ICOS),
- the FRB polypeptide is FRB T2098L.
- the first polypeptide comprises a CD8a transmembrane domain and the second polypeptide comprises a CD4 transmembrane domain.
- the CD8a transmembrane domain comprises the amino acid sequence as set forth in SEQ ID NO: 81.
- the CD8a transmembrane domain comprises the amino acid sequence as set forth in SEQ ID NO: 82.
- the CD8a transmembrane domain comprises the amino acid sequence as set forth in SEQ ID NO: 83.
- the spacer domain is a GGS spacer. In certain embodiments, the spacer domain is a GGR spacer.
- the hinge domain is a CD28 hinge domain. In certain embodiments, the hinge domain is a CD8a hinge domain. In certain embodiments, the hinge domain is a IgG4 hinge domain.
- the co-stimulatory domain of the second polypeptide is selected from a co-stimulatory molecule selected from the group consisting of: ICOS, MYD88, SLAMF6, IL2RP, and LAT.
- the co-stimulatory domain of the second polypeptide is an ICOS co-stimulatory domain.
- the co- stimulatory domain of the second polypeptide is a MYD88 co-stimulatory domain.
- the co-stimulatory domain of the second polypeptide is a SLAMF6 co- stimulatory domain.
- the co-stimulatory domain of the second polypeptide is a IL2R0 co-stimulatory domain.
- the co-stimulatory domain of the second polypeptide is a LAT co-stimulatory domain.
- the second polypeptide further comprises an anti-CLLl VHH antibody or fragment thereof.
- the second polypeptide comprises a G4S or GGS linker between the anti-CD33 VHH and anti-CLLl VHH, selected from the group consisting of (GiS)i (SEQ ID NO: 84), (G4S)2 (SEQ ID NO: 85), (G 4 S) 3 (SEQ ID NO: 86, (G 4 S) 4 (SEQ ID NO: 87), GGS, and 2xGGS (SEQ ID NO: 125).
- the G4S linker is a (G4S)I linker (SEQ ID NO: 84).
- the G4S linker is a (648)2 linker (SEQ ID NO: 85). In some embodiments, the G4S linker is a (648)3 linker (SEQ ID NO: 86). In some embodiments, the G4S linker is a (648)4 linker (SEQ ID NO: 87). In some embodiments, the linker is a GGS linker.
- the cell comprises a polypeptide complex comprising the first polypeptide, the second polypeptide, and a bridging factor associated with and disposed between the multimerization domains of the first and second polypeptides.
- the bridging factor is selected from the group consisting of: AP21967, sirolimus, everolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus, temsirolimus, umirolimus, and zotarolimus.
- the cell is a hematopoietic cell.
- the cell is a T cell, an ap T cell, or a y8 T cell.
- the cell is a CD3+, CD4+, and/or CD8+ cell.
- the cell is an immune effector cell.
- the cell is a cytotoxic T lymphocytes (CTLs), a tumor infiltrating lymphocytes (TILs), or a helper T cell.
- CTLs cytotoxic T lymphocytes
- TILs tumor infiltrating lymphocytes
- helper T cell a helper T cell.
- the cell is a natural killer (NK) cell or natural killer T (NKT) cell.
- NK natural killer
- NKT natural killer T
- the source of the cell is peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus issue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, or tumors.
- the FRB multimerization domain polypeptide or variant thereof and the FKBP multimerization domain polypeptide or variant thereof localize extracellularly when the first polypeptide and the second polypeptide are expressed.
- a non-natural cell expresses a first polypeptide and a second polypeptide set forth in any one of SEQ ID NOs: 22-63.
- a non-natural cell comprises the fusion polypeptide set forth in any one of SEQ ID NOs: 22-63.
- a fusion polypeptide comprises: a first polypeptide comprising an FRB multimerization domain polypeptide or variant thereof, a CD8a transmembrane domain or a CD28 transmembrane domain, a CD 137 co-stimulatory domain, and/or a CD3( ⁇ primary signaling domain; a polypeptide cleavage signal; and a second polypeptide comprising an anti-CD33 VHH antibody that has an amino acid sequence set forth in any one of SEQ ID NOs: 2-21, an FKBP multimerization domain polypeptide or variant thereof, a hinge domain selected from the group consisting of CD28, CD4, and IgG4 or a spacer domain selected from the group consisting of GGS and GGR, and a CD4 transmembrane domain or a CD28 transmembrane domain, and optionally one or more co-stimulatory domains selected from a co-stimulatory molecule selected from the group consisting of TNFR, CD28, MYD88,
- the FKBP multimerization domain is FKBP12.
- the FRB polypeptide is FRB T2098L.
- the first polypeptide comprises a CD8a transmembrane domain and the second polypeptide comprises a CD4 transmembrane domain.
- the CD8a transmembrane domain comprises the amino acid sequence as set forth in SEQ ID NO: 81.
- the CD8a transmembrane domain comprises the amino acid sequence as set forth in SEQ ID NO: 82.
- the CD8a transmembrane domain comprises the amino acid sequence as set forth in SEQ ID NO: 83.
- the spacer domain is a GGS spacer. In certain embodiments, the spacer domain is a GGR spacer.
- the hinge domain is a CD28 hinge domain. In certain embodiments, the hinge domain is a CD8a hinge domain. In certain embodiments, the hinge domain is a IgG4 hinge domain.
- the co-stimulatory domain of the second polypeptide is selected from a co-stimulatory molecule selected from the group consisting of: ICOS, MYD88, SLAMF6, IL2RP, and LAT.
- the co-stimulatory domain of the second polypeptide is an ICOS co-stimulatory domain.
- the co- stimulatory domain of the second polypeptide is a MYD88 co-stimulatory domain.
- the co-stimulatory domain of the second polypeptide is a SLAMF6 costimulatory domain.
- the co-stimulatory domain of the second polypeptide is a IL2R0 co-stimulatory domain.
- the co-stimulatory domain of the second polypeptide is a LAT co-stimulatory domain.
- the second polypeptide further comprises an anti-CLLl VHH antibody or fragment thereof.
- the second polypeptide comprises a G4S or GGS linker between the anti-CD33 VHH and anti-CLLl VHH, selected from the group consisting of (G4S)I (SEQ ID NO: 84), (G4S)2 (SEQ ID NO:85), (G 4 S) 3 (SEQ ID NO: 86), (G 4 S) 4 (SEQ ID NO: 87), GGS, and 2xGGS (SEQ ID NO: 125).
- the G4S linker is a (G4S)I linker (SEQ ID NO: 84).
- the G4S linker is a (G4S)2 linker (SEQ ID NO: 85). In some embodiments, the G4S linker is a (G4S) 3 linker (SEQ ID NO: 86). In some embodiments, the G4S linker is a (GrS)4 linker (SEQ ID NO: 87). In some embodiments, the linker is a GGS or 2xGGS linker (SEQ ID NO: 125).
- the polypeptide cleavage signal is a viral self-cleaving polypeptide.
- the polypeptide cleavage signal is a viral self-cleaving 2A polypeptide.
- the polypeptide cleavage signal is a viral self-cleaving polypeptide selected from the group consisting of: a foot-and-mouth disease virus (FMDV) (F2A) peptide, an equine rhinitis A virus (ERAV) (E2A) peptide, a Thosea asigna virus (TaV) (T2A) peptide, a porcine teschovirus-1 (PTV-1) (P2A) peptide, a Theilovirus 2A peptide, and an encephalomyocarditis virus 2A peptide.
- FMDV foot-and-mouth disease virus
- E2A equine rhinitis A virus
- TaV Thosea asigna virus
- PTV-1 porcine teschovirus-1
- P2A porcine teschovirus-1
- Theilovirus 2A peptide a Theilovirus 2A peptide
- a fusion polypeptide comprises an amino acid sequence set forth in any one of SEQ ID NOs: 22-63.
- a polynucleotide encodes a first or second polypeptide or a fusion polypeptide contemplated herein.
- a vector comprises a polynucleotide encoding a first or second polypeptide or a fusion polypeptide contemplated herein.
- the vector is an expression vector, a transposon, a piggyBAC transposon, a Sleeping Beauty transposon, a viral vector, an adenoviral vector, an adeno-associated viral (AAV) vector, a herpes virus vector, a vaccinia virus vector, a retroviral vector, or a lentiviral vector.
- a transposon a piggyBAC transposon
- a Sleeping Beauty transposon a viral vector
- an adenoviral vector an adeno-associated viral (AAV) vector
- AAV adeno-associated viral
- herpes virus vector a vaccinia virus vector
- retroviral vector a retroviral vector
- lentiviral vector lentiviral vector
- a cell comprises a first and second polypeptide, a fusion polypeptide, a polynucleotide, or a vector contemplated herein.
- the cell is a hematopoietic cell.
- the cell is an immune effector cell.
- the cell is a T cell, an T cell, or a y6 T cell.
- the cell expresses CD3+, CD4+, CD8+, or a combination thereof.
- the cell is a cytotoxic T lymphocyte (CTL), a tumor infiltrating lymphocyte (TIL), or a helper T cell.
- CTL cytotoxic T lymphocyte
- TIL tumor infiltrating lymphocyte
- helper T cell a helper T cell.
- the cell is a natural killer (NK) cell or natural killer T (NKT) cell.
- NK natural killer
- NKT natural killer T
- composition comprises a cell contemplated herein.
- a composition comprises a physiologically acceptable carrier and a cell contemplated herein.
- a method of treating a subject in need thereof comprises administering the subject an effective amount of a composition contemplated herein.
- a method of treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith comprising administering to the subject an effective amount of a composition contemplated herein.
- a method of treating a solid cancer comprising administering to the subject an effective amount of a composition contemplated herein.
- the solid cancer is selected from the group consisting of: lung cancer, squamous cell carcinoma, colorectal cancer, pancreatic cancer, breast cancer, thyroid cancer, bladder cancer, cervical cancer, esophageal cancer, ovarian cancer, gastric cancer endometrial cancer, or brain cancer.
- the solid cancer is a non-small cell lung carcinoma, head and neck squamous cell carcinoma, colorectal cancer, pancreatic cancer, breast cancer, thyroid cancer, bladder cancer, cervical cancer, esophageal cancer, ovarian cancer, gastric cancer endometrial cancer, gliomas, glioblastomas, or oligodendroglioma.
- a method of treating a hematological malignancy comprising administering to the subject an effective amount of a composition contemplated herein.
- the hematological malignancy is a leukemia, lymphoma, or multiple myeloma.
- the hematological malignancy is acute myelogenous leukemia (AML).
- AML acute myelogenous leukemia
- Figure 1A shows a cartoon of DARICs comprising a DARIC signaling component and a DARIC binding component comprising various transmembrane and co-stimulatory domains.
- Figure IB shows the percentage of transduced T cells that express CD33 DARIC binding components comprising various transmembrane and co-stimulatory domains, in transduced T cells as detected by CD33-Fc binding.
- Figure 1C shows IFNy secretion from T cells transduced with DARICs comprising CD33 DARIC binding components comprising various transmembrane and co-stimulatory domains or control cells with CD33 + A549 cells at an E:T ratio of 1 : 1 in the presence or absence of AP21967 for 24 hours.
- Figure ID shows IL-2 secretion from T cells transduced with DARICs comprising CD33 DARIC binding components comprising various transmembrane and co-stimulatory domains or control cells with CD33 + A549 cells at an E:T ratio of 1 : 1 in the presence or absence of AP21967 for 24 hours.
- Figure IE shows cytokine secretion (IFNy, IL-4, IL-6, IL-8, IL-10, IL- 13, IL-17A, and MIPip) from T cells transduced with DARICs comprising CD33 DARIC binding components comprising various transmembrane and co-stimulatory domains or control cells with CD33 + A549 cells at an E:T ratio of 1 : 1 in the presence or absence of AP21967 for 24 hours.
- DARICs comprising CD33 DARIC binding components comprising various transmembrane and co-stimulatory domains or control cells with CD33 + A549 cells at an E:T ratio of 1 : 1 in the presence or absence of AP21967 for 24 hours.
- Figure 2A shows a cartoon of DARICs comprising a DARIC signaling component comprising various hinge and transmembrane domains and a DARIC binding component comprising various hinge and transmembrane domains.
- Figure 2B shows the percentage of transduced T cells that express CD33 DARIC binding components comprising various hinge and transmembrane domains and the mean fluorescence intensity (MFI), as detected by CD33 -Fc binding.
- MFI mean fluorescence intensity
- Figure 2C shows the MFI of CD33 DARIC signaling components in T cells transduced with DARICs comprising binding components comprising various hinge and transmembrane domains, as detected by anti-FRB antibodies.
- Figure 2D shows IFNy secretion from T cells transduced with DARICs comprising CD33 DARIC binding components comprising various hinge and transmembrane domains or control cells with CD33 + A549 cells at an E:T ratio of 1 : 1 in the presence or absence of AP21967 for 24 hours.
- Figure 2E shows IL-2 secretion from T cells transduced with DARICs comprising CD33 DARIC binding components comprising various hinge and transmembrane domains or control cells with CD33 + A549 cells at an E:T ratio of 1 : 1 in the presence or absence of AP21967 for 24 hours.
- Figure 3A shows a cartoon of a tandem DARIC design with hinge and transmembrane elements identified for optimization.
- Figure 3B shows a cartoon of a tandem DARIC design with the VHH/VHH linker element identified for optimization.
- Figure 3C shows a cartoon of a tandem DARIC design with the VHH/VHH linker (SEQ ID NOs: 86 and 84) and transmembrane domain elements identified for optimization.
- Figure 4 shows a sequence alignment of a parental tandem DARIC and various DARICs with hinge and transmembrane modifications identified (SEQ ID NOs: 68-70 and 74).
- Figures 5A and 5B show the expression of hinge and transmembrane CD33-CLL1 tandem VHH DARIC variants in transduced T cells, as detected by CD33-Fc, CLLl-Fc, and anti-FRB binding.
- Figures 6A and 6B show IFNg secretion from hinge and transmembrane tandem VHH DARIC variants or control cells cultured with antigen positive cell lines at an E:T ratio of 1 : 1 in the presence of absence of rapamycin for 24 hours.
- Figures 7 shows a sequence alignment of tandem DARICs having varying VHH/VHH linker lengths (SEQ ID NOs: 126-130).
- Figures 8A and 8B show the expression of CD33-CLL1 tandem VHH DARIC variants in transduced T cells, as detected by CD33-Fc, CLLl-Fc, and anti-FRB binding.
- Figures 9A and 9B show IFNg secretion from tandem VHH DARIC linker variants or control cells cultured with antigen positive cell lines at an E:T ratio of 1 : 1 in the presence of absence of rapamycin for 24 hours.
- Figures 10 shows a sequence alignment of tandem DARICs having a MH or LYC containing transmembrane sequence and varying VHH/VHH linker lengths (SEQ ID NOs: 67, 72, 75, and 80).
- Figures 11A and 11B show the expression of combined hinge, transmembrane and linker CD33-CLL1 tandem VHH DARIC variants in transduced T cells, as detected by CD33-Fc, CLLl-Fc, and anti-FRB binding.
- Figures 12A and 12B show IFNg secretion from combined hinge, transmembrane and linker tandem VHH DARIC variants or control cells cultured with antigen positive cell lines at an E:T ratio of 1 : 1 in the presence of absence of rapamycin for 24 hours.
- SEQ ID NO: 1 sets forth the amino acid sequence for full-length human CD33.
- SEQ ID Nos: 2-21 set forth the amino acid sequences for an anti-CD33 VHH domains.
- SEQ ID NOs: 22-66 set forth the amino acid sequences for representative DARIC fusion polypeptides.
- SEQ ID NOs: 67-80 set forth the amino acid sequences for representative tandem DARIC fusion polypeptides.
- SEQ ID NOs: 81-83 set forth the amino acid sequences for representative CD8a transmembrane variants.
- SEQ ID NOs: 84-98 set forth the amino acid sequences for representative linkers.
- SEQ ID NOs: 99-123 set forth the amino acid sequences for representative selfcleaving peptides.
- Xaa if present, may refer to any amino acid or the absence of an amino acid. In preferred embodiments, XaaXaa refers to the amino acid sequence SS or KP.
- AML Acute myeloid leukemia
- CD33 is expressed on the majority of acute myeloid leukemia (AML) leukemic blasts and, possibly, leukemic stem cells. CD33 is a challenging target because of its low expression and slow internalization; these characteristics limit antibody-dependent cell- mediated cytotoxicity and intracellular drug accumulation and, consequently, the activity of unlabeled and toxin-carrying antibodies.
- AML acute myeloid leukemia
- the disclosure generally relates to improved compositions and methods for regulating the spatial and temporal control of adoptive cell therapies using dimerizing agent regulated immunoreceptor complexes (DARICs) that bind CD33.
- DARIC compositions and methods contemplated herein provide numerous advantages over CAR T cell therapies existing in the art, including but not limited to, both spatial and temporal control over immune effector cell signal transduction binding and signaling activities.
- DARIC temporal control primes the DARIC machinery for signaling through bridging factor mediated association of a DARIC binding component to a DARIC signaling component.
- DARIC spatial control engages the signaling machinery through recognition of CD33 by the DARIC binding domain of the DARIC binding component. In this manner, DARIC immune effector cells become activated when both a target cell expressing CD33 and a bridging factor are present.
- the disclosure contemplates anti-CD33 VHH DARICs that generate unique cytokine expression profiles and a robust anti-cancer response against cancers, e.g, AML that express CD33, e.g, full-length CD33 and/or a CD33 splice variant.
- a DARIC includes a polypeptide (DARIC signaling component) that comprises a multimerization domain polypeptide or variant thereof, a transmembrane domain, a co-stimulatory domain; and/or a primary signaling domain; and a polypeptide (DARIC binding component) that comprises an anti-CD33 VHH, a multimerization domain polypeptide or variant thereof, a hinge domain, a transmembrane domain; and optionally a co-stimulatory domain.
- DARIC signaling component that comprises a multimerization domain polypeptide or variant thereof, a transmembrane domain, a co-stimulatory domain; and/or a primary signaling domain
- DARIC binding component that comprises an anti-CD33 VHH, a multimerization domain polypeptide or variant thereof, a hinge domain, a transmembrane domain; and optionally a co-stimulatory domain.
- the DARIC binding and signaling components associate with one another through the bridging factor to form a functional
- the multimerization domains of the DARIC binding and DARIC signaling components are positioned extracellularly.
- Extracellular position of the multimerization domains provides numerous advantages over intracellular positioning including, but not limited to, more efficient positioning of the anti-CD33 VHH domain, higher temporal sensitivity to bridging factor regulation, and less toxicity due to ability to use non-immunosuppressive doses of particular bridging factors.
- Techniques for recombinant (z.e., engineered) DNA, peptide and oligonucleotide synthesis, immunoassays, tissue culture, transformation (e.g, electroporation, lipofection), enzymatic reactions, purification and related techniques and procedures may be generally performed as described in various general and more specific references in microbiology, molecular biology, biochemistry, molecular genetics, cell biology, virology and immunology as cited and discussed throughout the present specification.
- the term “about” or “approximately” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
- the term “about” or “approximately” refers a range of quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length ⁇ 15%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, or ⁇ 1% about a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
- a range e.g., 1 to 5, about 1 to 5, or about 1 to about 5, refers to each numerical value encompassed by the range.
- the range “1 to 5” is equivalent to the expression 1, 2, 3, 4, 5; or 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0; or 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0.
- the term “substantially” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher compared to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
- “substantially the same” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that produces an effect, e.g., a physiological effect, that is approximately the same as a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
- an “antigen (Ag)” refers to a compound, composition, or substance that can stimulate the production of antibodies or a T cell response in an animal, including compositions (such as one that includes a cancer-specific protein) that are injected or absorbed into an animal.
- exemplary antigens include but are not limited to lipids, carbohydrates, polysaccharides, glycoproteins, peptides, or nucleic acids.
- An antigen reacts with the products of specific humoral or cellular immunity, including those induced by heterologous antigens, such as the disclosed antigens.
- target antigen or “target antigen of interest” refers to a portion of CD33, that a binding domain contemplated herein, is designed to bind.
- the target antigen is an epitope of the amino acid sequence set forth in SEQ ID NO: 1.
- CD33 refers to a cell surface receptor also known as sialic-acid-binding immunoglobulin-like lectin 3 (SIGLEC-3) or GP67.
- SIGLEC-3 sialic-acid-binding immunoglobulin-like lectin 3
- GP67 a cell surface receptor also known as sialic-acid-binding immunoglobulin-like lectin 3 (SIGLEC-3) or GP67.
- SIGLEC-3 sialic-acid-binding immunoglobulin-like lectin 3
- CD33 has two Ig-like domains, one V-set domain and one C2-set domain.
- CD33 plays a role in mediating cellcell interactions and in maintaining immune cells in a resting state.
- CD33 recognizes and binds alpha-2,3- and more avidly alpha-2, 6-linked sialic acid-bearing glycans.
- CD33 Upon engagement of ligands such as Clq or sialylated glycoproteins, two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) located in CD33 cytoplasmic tail are phosphorylated by Src-like kinases such as LCK. These phosphorylations provide docking sites for the recruitment and activation of protein-tyrosine phosphatases PTPN6/SHP-1 and PTPN1 l/SHP-2.
- CD33 also has at least three identified splice variants.
- CDSS ⁇ 2 splice variant lacks the amino acid sequence encoded by exon 2 of the human CD33 gene (amino acids 13-139 of full-length CD33; e.g., NP_001076087.1, C2).
- CD33 7a splice variant lacks 54 carboxy-terminal amino acids due to an early translation stop signal residing in exon 7a (e.g., NP_001171079.1).
- CD33 AE2/7a lacks the amino acids encoded by exon 2 and 54 carboxy-terminal amino acids.
- CD33 is normally expressed on subsets of normal B cells and activated T cells and natural killer cells but is not expressed on hematopoietic stem cells or outside the hematopoietic system. Both full-length CD33 and/or CD33 splice variants are also expressed in acute myeloid leukemia (AML) blast cells in a majority of AML patients.
- AML acute myeloid leukemia
- an “antibody” refers to a binding agent that is a polypeptide comprising at least a light chain or heavy chain immunoglobulin variable region which specifically recognizes and binds an epitope of an antigen, such as a lipid, carbohydrate, polysaccharide, glycoprotein, peptide, or nucleic acid containing an antigenic determinant, such as those recognized by an immune cell.
- an antigen such as a lipid, carbohydrate, polysaccharide, glycoprotein, peptide, or nucleic acid containing an antigenic determinant, such as those recognized by an immune cell.
- VH refers to the variable region of an immunoglobulin heavy chain or antigen binding fragments thereof.
- a “heavy chain antibody” refers to an antibody that contains two VH domains and no light chains (Riechmann L. et al, J. Immunol. Methods 231 :25— 38 (1999); WO94/04678; WO94/25591; U.S. Patent No. 6,005,079).
- a “camelid antibody” refers to an antibody isolated from a Camel, Alpaca, or Llama that contains two VH domains and no light chains.
- a “humanized VHH” or “humanized camelid antibody” refers to a non- human VHH or camelid antibody that has undergone humanization to reduce potential immunogenicity of the antibody in human recipients.
- VHH refers an antibody fragment that contains the smallest known antigen-binding unit of the variable region of a heavy chain antibody (Koch-Nolte, et al, FASEB J., 21 : 3490-3498 (2007)).
- a “linker” refers to a plurality of amino acid residues between the various polypeptide domains added for appropriate spacing and conformation of the molecule.
- a linker separates one or more VHH domains, hinge domains, multimerization domains, transmembrane domains, co-stimulatory domains, and/or primary signaling domains.
- linkers suitable for use in particular embodiments contemplated herein include, but are not limited to the following amino acid sequences: GGG; DGGGS (SEQ ID NO: 89); TGEKP (SEQ ID NO: 90) (see, e.g., Liu et al., PNAS 5525-5530 (1997)); GGRR (SEQ ID NO: 91) (Pomerantz et al.
- linker comprises the following amino acid sequence: GSTSGSGKPGSGEGSTKG (SEQ ID NO: 98) (Cooper et al., Blood, 101(4): 1637-1644 (2003)).
- a “spacer domain,” refers to a polypeptide that separates two domains.
- a spacer domain moves a VHH domain away from the effector cell surface to enable proper cell/cell contact, antigen binding and activation (Patel et al., Gene Therapy, 1999; 6: 412-419).
- a spacer domain separates one or more VHH domains, multimerization domains, transmembrane domains, co-stimulatory domains, and/or primary signaling domains.
- the spacer domain may be derived either from a natural, synthetic, semi-synthetic, or recombinant source.
- a spacer domain is a portion of an immunoglobulin, including, but not limited to, one or more heavy chain constant regions, e.g., CH2 and CH3.
- the spacer domain can include the amino acid sequence of a naturally occurring immunoglobulin hinge region or an altered immunoglobulin hinge region.
- Illustrative examples of spacer domains suitable for use in particular embodiments contemplated herein include but are not limited to GGS and GGR.
- polypeptides refers to a polypeptide that plays a role in positioning the antigen binding domain away from the effector cell surface to enable proper cell/cell contact, antigen binding and activation.
- polypeptides may comprise one or more hinge domains between the binding domain and the multimerization domain, between the binding domain and the transmembrane domain (TM), or between the multimerization domain and the transmembrane domain.
- the hinge domain may be derived either from a natural, synthetic, semi-synthetic, or recombinant source.
- the hinge domain can include the amino acid sequence of a naturally occurring immunoglobulin hinge region or an altered immunoglobulin hinge region.
- hinge domains suitable for use in particular embodiments contemplated herein include but are not limited to a CD28, CD4, IgG2, or IgG4 hinge or suitable combinations thereof.
- hinge domains suitable for use in particular embodiments contemplated herein include but are not limited to a alpha, beta, gamma, or delta chain of the T-cell receptor, CD2, CD35, CD3e, CD3y, CD3 ⁇ , CD4, CD5, CD8a, CD9, CD 16, CD22, CD27, CD28, CD33, CD37, CD40, CD45, CD64, CD80, CD86, CD 134, CD137, CD152, CD154, CD244, CD278, amnionless (AMN), programmed cell death 1 (PDCD1), TNRF2, TNFRS14, TNFRS25, TLR2, TLR4, TLR5, TIM1, SlamFl, SlamF5, and SlamF6.
- APN amnionless
- a “multimerization domain,” as used herein, refers to a polypeptide that preferentially interacts or associates with another different polypeptide directly or via a bridging molecule, e.g., a chemically inducible dimerizer, wherein the interaction of different multimerization domains substantially contributes to or efficiently promotes multimerization (z.e., the formation of a dimer, trimer, or multipartite complex, which may be a homodimer, heterodimer, homotrimer, heterotrimer, homomultimer, heteromultimer).
- a multimerization domain may be derived either from a natural, synthetic, semi-synthetic, or recombinant source.
- multimerization domains suitable for use in particular embodiments contemplated herein include an FK506 binding protein (FKBP) polypeptide or variants thereof, an FKBP-rapamycin binding (FRB) polypeptide or variants thereof, a calcineurin polypeptide or variants thereof, a cyclophilin polypeptide or variants thereof, a bacterial dihydrofolate reductase (DHFR) polypeptide or variants thereof, a PYRl-like 1 (PYL1) polypeptide or variants thereof, an abscisic acid insensitive 1 (ABI1) polypeptide or variants thereof, a GIB 1 polypeptide or variants thereof, or a GAI polypeptide or variants thereof.
- FKBP FK506 binding protein
- a calcineurin polypeptide or variants thereof a cyclophilin polypeptide or variants thereof
- DHFR bacterial dihydrofolate reductase
- FKBP-rapamycin binding polypeptide refers to an FRB polypeptide.
- the FRB polypeptide is an FKBP12-rapamycin binding polypeptide.
- FRB polypeptides suitable for use in particular embodiments contemplated herein generally contain at least about 85 to about 100 amino acid residues.
- the FRB polypeptide comprises a 93 amino acid sequence Ile-2021 through Lys -2113 and a mutation of T2098L (T82L is equivalent position in 93 amino acid FRB polypeptide), with reference to GenBank Accession No. L34075.1.
- An FRB polypeptide contemplated herein binds to an FKBP polypeptide through a bridging factor, thereby forming a ternary complex.
- FK506 binding protein refers to an FKBP polypeptide.
- the FKBP polypeptide is an FKBP12 polypeptide or an FKBP12 polypeptide comprising an F36V mutation.
- an FKBP domain may also be referred to as a “rapamycin binding domain”.
- Information concerning the nucleotide sequences, cloning, and other aspects of various FKBP species is known in the art (see, e.g., Staendart el al., Nature 346:611, 1990 (human FKBP12); Kay, Biochem. J. 314:361, 1996).
- An FKBP polypeptide contemplated herein binds to an FRB polypeptide through a bridging factor, thereby forming a ternary complex.
- a “bridging factor” refers to a molecule that associates with and that is disposed between two or more multimerization domains.
- multimerization domains substantially contribute to or efficiently promote formation of a polypeptide complex only in the presence of a bridging factor.
- multimerization domains do not contribute to or do not efficiently promote formation of a polypeptide complex in the absence of a bridging factor.
- bridging factors suitable for use in particular embodiments contemplated herein include, but are not limited to AP21967, rapamycin (sirolimus) or a rapalog thereof, coumermycin or a derivative thereof, gibberellin or a derivative thereof, abscisic acid (ABA) or a derivative thereof, methotrexate or a derivative thereof, cyclosporin A or a derivative thereof, FKCsA or a derivative thereof, trimethoprim (Tmp)-synthetic ligand for FKBP (SLF) or a derivative thereof, or any combination thereof.
- AP21967 rapamycin (sirolimus) or a rapalog thereof, coumermycin or a derivative thereof, gibberellin or a derivative thereof, abscisic acid (ABA) or a derivative thereof, methotrexate or a derivative thereof, cyclosporin A or a derivative thereof, FKCsA or a derivative thereof, trimethoprim (
- Rapamycin analogs include, but are not limited to, those disclosed in U.S. Pat. No. 6,649,595, which rapalog structures are incorporated herein by reference in their entirety.
- a bridging factor is a rapalog with substantially reduced immunosuppressive effect as compared to rapamycin.
- rapalogs suitable for use in particular embodiments contemplated herein include, but are not limited to, everolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus, temsirolimus, umirolimus, and zotarolimus.
- a “substantially reduced immunosuppressive effect” refers to at least less than 0.1 to 0.005 times the immunosuppressive effect observed or expected for the same dose measured either clinically or in an appropriate in vitro (e.g., inhibition of T cell proliferation) or in vivo surrogate of human immunosuppressive activity.
- a “transmembrane domain” or “TM domain” is a domain that anchors a polypeptide to the plasma membrane of a cell.
- the TM domain may be derived either from a natural, synthetic, semi-synthetic, or recombinant source.
- transmembrane domains suitable for use in particular embodiments contemplated herein include, but are not limited to a CD8a transmembrane domain, a CD4 transmembrane domain, or a CD28 transmembrane domain.
- transmembrane domains suitable for use in particular embodiments contemplated herein include but are not limited to a alpha, beta, gamma, or delta chain of the T-cell receptor, CD2, CD35, CD3s, CD3y, CD3 ⁇ , CD4, CD5, CD8a, CD9, CD 16, CD22, CD27, CD28, CD33, CD37, CD40, CD45, CD64, CD80, CD86, CD 134, CD137, CD152, CD154, CD244, CD278, amnionless (AMN), programmed cell death 1 (PDCD1), TNRF2, TNFRS14, TNFRS25, TLR2, TLR4, TLR5, TIM1, SlamFl, SlamF5, and SlamF6.
- APN amnionless
- effector function refers to a specialized function of an immune effector cell. Effector function includes, but is not limited to, activation, cytokine production, proliferation and cytotoxic activity, including the release of cytotoxic factors, or other cellular responses elicited with antigen binding to the receptor expressed on the immune effector cell.
- intracellular signaling domain refers to the portion of a protein which transduces the effector function signal and that directs the cell to perform a specialized function. While usually the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire domain. To the extent that a truncated portion of an intracellular signaling domain is used, such truncated portion may be used in place of the entire domain as long as it transduces an effector function signal.
- intracellular signaling domain is meant to include any truncated portion of an intracellular signaling domain necessary or sufficient to transduce an effector function signal.
- T cell activation can be said to be mediated by two distinct classes of intracellular signaling domains: primary signaling domains that initiate antigen-dependent primary activation through the TCR (e.g., a TCR/CD3 complex) and co-stimulatory signaling domains that act in an antigen-independent manner to provide a secondary or co-stimulatory signal.
- primary signaling domains that initiate antigen-dependent primary activation through the TCR (e.g., a TCR/CD3 complex)
- co-stimulatory signaling domains that act in an antigen-independent manner to provide a secondary or co-stimulatory signal.
- a “primary signaling domain” refers to an intracellular signaling domain that regulates the primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way.
- Primary signaling domains that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs.
- ITAM containing primary signaling domains include, but are not limited to those derived from FcRy, FcRp, CD3y, CD38, CD3s, CD31 CD22, CD79a, CD79b, and CD66d.
- co-stimulatory signaling domain refers to an intracellular signaling domain of a co-stimulatory molecule.
- Co- stimulatory molecules are cell surface molecules other than antigen receptors or Fc receptors that provide a second signal required for efficient activation and function of T lymphocytes upon binding to antigen.
- co-stimulatory molecules from which co-stimulatory domains may be isolated include, but are not limited to: TNFR, CD28, MYD88, CD40, CD4, CD278 (ICOS), interleukin 2 receptor beta (IL2RP), signaling lymphocytic activation molecule family member 6 (SLAMF6), and Linker for activation of T-cells family member 1 (LAT).
- TNFR TNFR
- CD28 CD28
- MYD88 CD40
- CD4, CD278 CD278
- IL2RP interleukin 2 receptor beta
- SLAMF6 signaling lymphocytic activation molecule family member 6
- LAT Linker for activation of T-cells family member 1
- co-stimulatory molecules from which co- stimulatory domains may be isolated include, but are not limited to: Toll-like receptor 1 (TLR1), TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, caspase recruitment domain family member 11 (CARD11), CD2, CD4, CD7, CD27, CD28, CD28-YMFM, CD28- H, CD30, CD40, CD54 (ICAM), CD83, CD94, CD134 (0X40), CD137 (4- IBB), CD278 (ICOS), DNAX-Activation Protein 10 (DAP10), IL2RP, Linker for activation of T-cells family member 1 (LAT), SH2 Domain-Containing Leukocyte Protein Of 76 kD (SLP76), T cell receptor associated transmembrane adaptor 1 (TRAT1), TNFR2, TNF receptor superfamily member 14 (TNFRS14; FTVEM), TNF receptor superfamily member 18 (TN
- TLR1 Toll
- an “immune disorder” refers to a disease that evokes a response from the immune system.
- the term “immune disorder” refers to a cancer, an autoimmune disease, or an immunodeficiency.
- cancer relates generally to a class of diseases or conditions in which abnormal cells divide without control and can invade nearby tissues.
- malignant refers to a cancer in which a group of tumor cells display one or more of uncontrolled growth (i.e., division beyond normal limits), invasion i.e., intrusion on and destruction of adjacent tissues), and metastasis i.e., spread to other locations in the body via lymph or blood).
- metastasize refers to the spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.” The metastatic tumor contains cells that are like those in the original (primary) tumor.
- Benign or “non-malignanf ’ refers to tumors that may grow larger but do not spread to other parts of the body. Benign tumors are self-limited and typically do not invade or metastasize.
- a “cancer cell” refers to an individual cell of a cancerous growth or tissue. Cancer cells include both solid cancers and liquid cancers.
- a “tumor” or “tumor cell” refers generally to a swelling or lesion formed by an abnormal growth of cells, which may be benign, pre-malignant, or malignant. Most cancers form tumors, but liquid cancers, e.g., leukemia, do not necessarily form tumors. For those cancers that form tumors, the terms cancer (cell) and tumor (cell) are used interchangeably.
- the amount of a tumor in an individual is the “tumor burden” which can be measured as the number, volume, or weight of the tumor.
- relapse refers to the diagnosis of return, or signs and symptoms of return, of a cancer after a period of improvement or remission.
- Remission is also referred to as “clinical remission,” and includes both partial and complete remission. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although cancer still may be in the body.
- Refractory refers to a cancer that is resistant to, or non-responsive to, therapy with a particular therapeutic agent.
- a cancer can be refractory from the onset of treatment (i.e., non- responsive to initial exposure to the therapeutic agent), or as a result of developing resistance to the therapeutic agent, either over the course of a first treatment period or during a subsequent treatment period.
- the terms “individual” and “subject” are often used interchangeably and refer to any animal that exhibits a symptom of cancer or other immune disorder that can be treated with the compositions and methods contemplated elsewhere herein.
- Suitable subjects include laboratory animals (such as mouse, rat, rabbit, or guinea pig), farm animals, and domestic animals or pets (such as a cat or dog).
- laboratory animals such as mouse, rat, rabbit, or guinea pig
- farm animals such as a cat or dog
- domestic animals or pets such as a cat or dog
- Non-human primates and, preferably, human patients are included.
- Typical subjects include human patients that have, have been diagnosed with, or are at risk or having, cancer or another immune disorder.
- the term “patient” refers to a subject that has been diagnosed with cancer or another immune disorder that can be treated with the compositions and methods disclosed elsewhere herein.
- treatment includes any beneficial or desirable effect on the symptoms or pathology of a disease or pathological condition, and may include even minimal reductions in one or more measurable markers of the disease or condition being treated. Treatment can involve optionally either the reduction of the disease or condition, or the delaying of the progression of the disease or condition, e.g., delaying tumor outgrowth. “Treatment” does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof.
- prevention indicates an approach for preventing, inhibiting, or reducing the likelihood of the occurrence or recurrence of, a disease or condition. It also refers to delaying the onset or recurrence of a disease or condition or delaying the occurrence or recurrence of the symptoms of a disease or condition. As used herein, “prevention” and similar words also includes reducing the intensity, effect, symptoms and/or burden of a disease or condition prior to onset or recurrence of the disease or condition.
- the phrase “ameliorating at least one symptom of’ refers to decreasing one or more symptoms of the disease or condition for which the subject is being treated.
- the disease or condition being treated is a cancer, wherein the one or more symptoms ameliorated include, but are not limited to, weakness, fatigue, shortness of breath, easy bruising and bleeding, frequent infections, enlarged lymph nodes, distended or painful abdomen (due to enlarged abdominal organs), bone or joint pain, fractures, unplanned weight loss, poor appetite, night sweats, persistent mild fever, and decreased urination (due to impaired kidney function).
- “enhance” or “promote,” or “increase” or “expand” refers generally to the ability of a composition contemplated herein to produce, elicit, or cause a greater physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule/composition.
- a measurable physiological response may include an increase in T cell expansion, activation, persistence, cytokine secretion, and/or an increase in cancer cell killing ability, among others apparent from the understanding in the art and the description herein.
- An “increased” or “enhanced” amount is typically a “statistically significant” amount, and may include an increase that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7. 1.8, etc.) the response produced by vehicle or a control composition.
- a decrease refers generally to the ability of composition contemplated herein to produce, elicit, or cause a lesser physiological response (i.e., downstream effects) compared to the response caused by either vehicle or a control molecule/composition.
- a “decrease” or “reduced” amount is typically a “statistically significant” amount, and may include a decrease that is 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30 or more times (e.g., 500, 1000 times) (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7. 1.8, etc.) the response (reference response) produced by vehicle, a control composition, or the response in a particular cell lineage.
- ком ⁇ онент or “preserve,” or “maintenance,” or “no change,” or “no substantial change,” or “no substantial decrease” refers generally to the ability of a composition contemplated herein to produce, elicit, or cause a substantially similar or comparable physiological response (i.e., downstream effects) in a cell, as compared to the response caused by either vehicle, a control molecule/composition, or the response in a particular cell lineage.
- a comparable response is one that is not significantly different or measurable different from the reference response.
- a DARIC receptor comprising an anti-CD33 VHH domain that redirects cytotoxicity of immune effector cells toward cancer cells expressing CD33 is contemplated.
- CD33 VHH DARIC receptor refers to one or more non-naturally occurring polypeptides that transduces an immunostimulatory signal in an immune effector cell upon exposure to a target cell expressing full-length CD33 or a CD33 splice variant and a multimerizing agent or bridging factor, e.g., stimulating immune effector cell activity and function, increasing production and/or secretion of proinflammatory cytokines.
- a CD33 VHH DARIC is a multi-chain chimeric receptor comprising a DARIC signaling component and a DARIC binding component comprising a VHH domain that recognizes full-length CD33 and/or a CD33 splice variant.
- DARIC signaling component CD33 DARIC signaling component
- DARIC signaling polypeptide DARIC signaling polypeptide
- DARIC signaling polypeptide a polypeptide comprising one or more multimerization domains, a transmembrane domain, and one or more intracellular signaling domains.
- a DARIC signaling component comprises a multimerization domain, a transmembrane domain, a co-stimulatory domain and/or a primary signaling domain.
- a DARIC signaling component comprises a first multimerization domain, a first transmembrane domain, a first co-stimulatory domain and/or a primary signaling domain.
- a DARIC signaling component comprises one or more multimerization domains.
- multimerization domains suitable for use in particular CD33 DARIC signaling components contemplated herein include, but are not limited to, an FK506 binding protein (FKBP) polypeptide or variants thereof, an FKBP-rapamycin binding (FRB) polypeptide or variants thereof, a calcineurin polypeptide or variants thereof, a cyclophilin polypeptide or variants thereof, a bacterial dihydrofolate reductase (DHFR) polypeptide or variants thereof, a PYRl-like 1 (PYL1) polypeptide or variants thereof and an abscisic acid insensitive 1 (ABI1) polypeptide or variants thereof.
- FKBP FK506 binding protein
- a calcineurin polypeptide or variants thereof a cyclophilin polypeptide or variants thereof
- DHFR bacterial dihydrofolate reductase
- ABSI1 abscisic acid insensitive 1
- a CD33 DARIC signaling component comprises an FRB polypeptide.
- a CD33 DARIC signaling component comprises an FRB polypeptide comprising a T2098L mutation, or variant thereof. In certain preferred embodiments, a CD33 DARIC signaling component comprises an FKBP12 polypeptide or variant thereof.
- a CD33 VHH DARIC signaling component comprises a hinge domain.
- Illustrative hinge domains suitable for use in a CD33 VHH DARIC signaling component described herein include the hinge region derived from the extracellular regions of CD28, CD8a, and IgG4, which may be wild-type hinge regions from these molecules or may be altered.
- the hinge region is derived from the extracellular regions of CD28.
- the hinge region is derived from the extracellular regions of CD8a.
- the hinge region is derived from the extracellular regions of IgG4.
- a CD33 VHH DARIC signaling component comprises a spacer domain.
- the spacer domain is 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length.
- the spacer comprises the amino acid sequence GGS or GGR.
- a DARIC signaling component comprises a transmembrane domain.
- a DARIC signaling component comprises a hinge domain and a transmembrane domain.
- transmembrane domains suitable for use in particular CD33 DARIC signaling components contemplated herein include, but are not limited to, the transmembrane region(s) of the alpha, beta, gamma, or delta chain of a T-cell receptor, CD3e, CD3i CD4, CD5, CD8a, CD9, CD 16, CD22, CD27, CD28, CD33, CD37, CD45, CD64, CD71, CD80, CD86, CD 134, CD137, CD152, CD 154, amnionless (AMN), and programmed cell death 1 (PDCD1).
- a CD33 DARIC signaling component comprises a CD28 transmembrane domain.
- a CD33 DARIC signaling component comprises a CD8a transmembrane domain.
- a DARIC signaling component comprises a linker that links the C-terminus of the transmembrane domain to the N-terminus of an intracellular signaling domain.
- a short oligo- or poly-peptide linker preferably between 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length links the transmembrane domain and an intracellular signaling domain.
- a glycine-serine based linker provides a particularly suitable linker.
- DARIC signaling components contemplated in particular embodiments herein comprise one or more intracellular signaling domains.
- a CD33 DARIC signaling component comprises one or more co-stimulatory signaling domains and/or a primary signaling domain.
- the intracellular signaling domain comprises an immunoreceptor tyrosine activation motif (IT AM).
- a CD33 DARIC signaling component comprises a CD3( ⁇ primary signaling domain and one or more co-stimulatory signaling domains.
- the primary signaling and co-stimulatory signaling domains may be linked in any order in tandem to the carboxyl terminus of the transmembrane domain.
- co-stimulatory domains suitable for use in particular CD33 DARIC signaling components contemplated herein include, but are not limited to those domains isolated from the following co-stimulatory molecules: Toll-like receptor 1 (TLR1), TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, caspase recruitment domain family member 11 (CARD11), CD2, CD4, CD7, CD27, CD28, CD28- YMFM, CD28-H, CD30, CD40, CD54 (ICAM), CD83, CD94, CD134 (0X40), CD137 (4- 1BB), CD278 (ICOS), DNAX- Activation Protein 10 (DAP10), IL2R0, Linker for activation of T-cells family member 1 (LAT), SH2 Domain-Containing Leukocyte Protein Of 76 kD (SLP76), T cell receptor associated transmembrane adaptor 1 (TRAT1), TNFR2, TNF receptor super
- TLR1
- a CD33 DARIC signaling component contemplated herein comprises a signal peptide.
- signal peptides suitable for use in particular CD33 DARIC signaling components include but are not limited to signal polypeptides derived from IgG heavy chain (e.g, from IgGl, IgG2), an IgK light chain (e.g., IgKVIII, IgKB7), CD8a, CD33, IL-2, IFNy, GM-CSF, osteonectin (BM40, SPARC), SECRECON, tissue polypeptide antigen (TPA), CHYMOTRSYPSINOGEN, TRYPSINOGEN-2, Argininosuccinate synthase (ASS), INSULIN, human serum albumin (HSA), or oncostatin M (OSM).
- a CD33 DARIC signaling component comprises a CD8a signal polypeptide.
- a CD33 DARIC signaling component comprises one or more co-stimulatory signaling domains selected from the group consisting of CD28, CD137, and CD134.
- a CD33 DARIC signaling component comprises a CD137 co-stimulatory domain and a CD3( ⁇ primary signaling domain.
- a CD33 DARIC signaling component comprises an FRB T2098L multimerization domain, a CD8a transmembrane domain, a CD 137 co- stimulatory domain and a CD3( ⁇ primary signaling domain.
- a CD33 VHH DARIC signaling component comprises an amino acid sequence set forth in one of SEQ ID NOs: 22-63. 2.
- a “DARIC binding component,” “DARIC binding polypeptide,” “CD33 VHH DARIC binding component,” or “CD33 VHH DARIC binding polypeptide” are used interchangeably and refer to a polypeptide comprising an anti-CD33 VHH domain, and one or more multimerization domains.
- the CD33 VHH DARIC binding component comprises an anti-CD33 VHH domain, a multimerization domain, a hinge domain, a transmembrane domain, and optionally one or more co-stimulatory domains.
- the CD33 VHH DARIC binding component comprises one or more anti-CD33 VHH domains.
- the anti- CD33 VHH domain is a humanized camelid VHH comprising amino acid sequence set forth in any one of SEQ ID NOs: 3-6, 10-11, 13-16, and 20-21.
- the anti-CD33 VHH domain is a humanized camelid VHH comprising amino acid sequence set forth in SEQ ID NO: 10.
- the anti-CD33 VHH domain is a humanized camelid VHH comprising amino acid sequence set forth in SEQ ID NO: 20.
- a DARIC binding component comprises one or more multimerization domains.
- multimerization domains suitable for use in particular CD33 VHH DARIC binding components contemplated herein include, but are not limited to, an FKBP polypeptide or variants thereof, an FRB polypeptide or variants thereof, a calcineurin polypeptide or variants thereof, a cyclophilin polypeptide or variants thereof, a DHFR polypeptide or variants thereof, a PYL1 polypeptide or variants thereof and an ABH polypeptide or variants thereof.
- a CD33 VHH DARIC binding component comprises an FRB polypeptide or variant thereof and a DARIC signaling component comprises an FKBP polypeptide or variant thereof.
- a CD33 VHH DARIC binding component comprises an FRB polypeptide comprising a T2098L mutation, or variant thereof and a DARIC signaling component comprises an FKBP12 polypeptide or variant thereof.
- a CD33 VHH DARIC binding component comprises an FKBP polypeptide or variant thereof and a DARIC signaling component comprises an FRB polypeptide, or variant thereof.
- a CD33 VHH DARIC binding component comprises an FKBP12 polypeptide, or variant thereof and a DARIC signaling component comprises an FRB polypeptide comprising a T2098L mutation, or variant thereof.
- a CD33 VHH DARIC binding component comprises a hinge domain.
- Illustrative hinge domains suitable for use in a CD33 VHH DARIC binding component described herein include the hinge region derived from the extracellular regions of CD28, CD4, or IgG4, which may be wild-type hinge regions from these molecules or may be altered.
- the hinge is a CD4 hinge.
- the hinge region is derived from the extracellular regions of CD28.
- the hinge region is derived from the extracellular regions of CD8a.
- the hinge region is derived from the extracellular regions of IgG4.
- a CD33 VHH DARIC binding component comprises a spacer domain.
- the spacer domain is 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length.
- the spacer comprises the amino acid sequence GGS or GGR.
- a DARIC binding component comprises a transmembrane domain.
- a DARIC binding component comprises a hinge domain and a transmembrane domain.
- the transmembrane domain may be the same as the transmembrane domain used in the DARIC signaling component.
- the transmembrane domain may be different from the transmembrane domain used in the DARIC signaling component.
- the transmembrane domain is CD4 transmembrane domain, a CD28 transmembrane domain, or a CD8a transmembrane domain.
- a CD33 VHH DARIC binding component comprises CD4 hinge and transmembrane domains.
- a short oligo- or poly-peptide linker preferably between 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids in length links the transmembrane domain and the intracellular signaling domain.
- a glycine-serine based linker provides a particularly suitable linker.
- a CD33 VHH DARIC binding component comprises a co-stimulatory signaling domain.
- the co-stimulatory domain is isolated from TNFR, CD28, MYD88, CD40, CD4, CD278 (ICOS), signaling lymphocytic activation molecule family member 6 (SLAMF6), IL2Rp, and Linker for activation of T-cells family member 1 (LAT).
- the co-stimulatory domain is isolated from MYD88, ICOS, SLAMF6, and LAT.
- the co-stimulatory domain of the second polypeptide is an ICOS co-stimulatory domain. In some embodiments, the co- stimulatory domain of the second polypeptide is a MYD88 co-stimulatory domain. In some embodiments, the co-stimulatory domain of the second polypeptide is a SLAMF6 co- stimulatory domain. In some embodiments, the co-stimulatory domain of the second polypeptide is a IL2RP co-stimulatory domain. In some embodiments, the co-stimulatory domain of the second polypeptide is a LAT co-stimulatory domain.
- the second polypeptide further comprises an anti-CLLl VHH antibody or fragment thereof.
- the second polypeptide comprises a G4S (SEQ ID NOs: 84-87) or GGS linker between the anti-CD33 VHH and anti-CLLl VHH, selected from the group consisting of (G4S)I (SEQ ID NO: 84), (G4S)2 (SEQ ID NO: 85), (G 4 S) 3 (SEQ ID NO:86), (G 4 S) 4 (SEQ ID NO: 87), GGS, and 2xGGS (SEQ ID NO: 124).
- the G4S linker is a (G4S)I linker (SEQ ID NO: 84).
- the G4S linker is a (G4S)2 linker (SEQ ID NO: 85). In some embodiments, the G4S linker is a (G4S) 3 linker (SEQ ID NO: 86). In some embodiments, the G4S linker is a (648)4 linker (SEQ ID NO: 87). In some embodiments, the linker is a GGS or 2xGGS linker (SEQ ID NO: 125).
- a DARIC binding component contemplated herein comprises a signal peptide.
- signal peptides suitable for use in particular CD33 DARIC binding components include but are not limited to signal polypeptides derived from IgG heavy chain (e.g., from IgGl, IgG2), an IgK light chain (e.g, IgKVIII, IgKB7), CD8a, CD33, IL-2, IFNy, GM-CSF, osteonectin (BM40, SPARC), SECRECON, tissue polypeptide antigen (TPA), CHYMOTRSYPSINOGEN, TRYPSINOGEN-2, Argininosuccinate synthase (ASS), INSULIN, human serum albumin (HSA), or oncostatin M (OSM).
- IgG heavy chain e.g., from IgGl, IgG2
- IgK light chain e.g, IgKVIII, IgKB7
- CD8a derived from Ig
- a CD33 VHH DARIC binding component comprises a CD8a signal polypeptide.
- a CD33 VHH DARIC binding component comprises a VHH domain that binds to CD33, an FKBP12 multimerization domain, a hinge domain from CD28, CD4, or IgG4 or a spacer domain comprising GGS or GGR; and a CD4 transmembrane domain or a CD28 transmembrane domain; and optionally, a costimulatory domain from MYD88, ICOS, SLAMF6, and LAT.
- a CD33 VHH DARIC binding component comprises a VHH domain that binds to CD33, an FKBP12 multimerization domain, a hinge domain from CD28, CD4, or IgG4 or a spacer domain comprising GGS or GGR; and a CD4 transmembrane domain and optionally, a MYD88 co-stimulatory domain.
- a CD33 VHH DARIC binding component comprises a VHH domain that binds to CD33, an FKBP12 multimerization domain, a CD4 hinge and transmembrane domain and optionally, a MYD88 co-stimulatory domain.
- a CD33 VHH DARIC binding component comprises the amino acid sequence set forth in any one of SEQ ID NO: 22-63. 5.
- Bridging factors contemplated in particular embodiments herein mediate or promote the association of a CD33 DARIC signaling component with a CD33 VHH DARIC binding component through multimerization domains in the respective components.
- a bridging factor associates with and is disposed between the multimerization domains to promote association of a CD33 DARIC signaling component and a CD33 VHH DARIC binding component.
- the CD33 VHH DARIC binding component and the CD33 DARIC signaling component associate and initiate immune effector cell activity against a target cell when the CD33 VHH DARIC binding component binds CD33 expressed on the target cell.
- the CD33 VHH DARIC binding component does not associate with the CD33 DARIC signaling component and the CD33 VHH DARIC is inactive.
- a CD33 DARIC signaling component and a CD33 VHH DARIC binding component comprise a cognate pair of multimerization domains selected from the group consisting of: FKBP and FKBP12-rapamycin binding (FRB), FKBP and calcineurin, FKBP and cyclophilin, FKBP and bacterial dihydrofolate reductase (DHFR), calcineurin and cyclophilin, and PYRl-like 1 (PYL1) and abscisic acid insensitive 1 (ABH).
- FKBP and FKBP12-rapamycin binding FKBP and calcineurin
- FKBP and cyclophilin FKBP and bacterial dihydrofolate reductase (DHFR)
- DHFR bacterial dihydrofolate reductase
- calcineurin and cyclophilin calcineurin and cyclophilin
- the multimerization domains of CD33 VHH DARIC signaling and binding components associate with a bridging factor selected from the group consisting of: rapamycin or a rapalog thereof, coumermycin or a derivative thereof, gibberellin or a derivative thereof, abscisic acid (ABA) or a derivative thereof, methotrexate or a derivative thereof, cyclosporin A or a derivative thereof, FK506/cyclosporin A (FKCsA) or a derivative thereof, and trimethoprim (Tmp)-synthetic ligand for FK506 binding protein (FKBP) (SLF) or a derivative thereof.
- a bridging factor selected from the group consisting of: rapamycin or a rapalog thereof, coumermycin or a derivative thereof, gibberellin or a derivative thereof, abscisic acid (ABA) or a derivative thereof, methotrexate or a derivative thereof, cyclosporin A or a derivative thereof
- a CD33 DARIC signaling component and a CD33 VHH DARIC binding component comprise one or more FRB and/or FKBP multimerization domains or variants thereof.
- a CD33 DARIC signaling component comprises an FRB multimerization domain or variant thereof and a CD33 VHH DARIC binding component comprises an FKBP multimerization domain or variant thereof.
- a CD33 DARIC signaling component comprises an FRB T2098L multimerization domain or variant thereof and a CD33 VHH DARIC binding component comprises an FKBP12 or FKBP12 F36V multimerization domains or variant thereof.
- bridging factors suitable for use in particular embodiments contemplated herein include, but are not limited to, AP1903, AP20187, AP21967 (also known as C-16-(S)-7-methylindolerapamycin), everolimus, novolimus, pimecrolimus, ridaforolimus, tacrolimus, temsirolimus, umirolimus, and zotarolimus.
- the bridging factor is AP21967.
- the bridging factor is a non-immunosuppressive dose of sirolimus (rapamycin).
- polypeptides are contemplated herein, including, but not limited to, CD33 VHH DARICs, CD33 VHH DARIC binding components, CD33 DARIC signaling components, and fragments thereof.
- a polypeptide comprises an amino acid sequence set forth in any one of SEQ ID NOs: 22-63.
- Polypeptide,” “peptide” and “protein” are used interchangeably, unless specified to the contrary, and according to conventional meaning, i.e., as a sequence of amino acids.
- a “polypeptide” includes fusion polypeptides and other variants. Polypeptides can be prepared using any of a variety of well-known recombinant and/or synthetic techniques.
- Polypeptides are not limited to a specific length, e.g., they may comprise a full-length protein sequence, a fragment of a full-length protein, or a fusion protein, and may include post-translational modifications of the polypeptide, for example, glycosylations, acetylations, phosphorylations and the like, as well as other modifications known in the art, both naturally occurring and non-naturally occurring.
- fusion polypeptides, polypeptides, fragments and other variants thereof are prepared, obtained, or isolated from one or more human polypeptides.
- an isolated polypeptide is a synthetic polypeptide, a semi -synthetic polypeptide, or a polypeptide obtained or derived from a recombinant source.
- Polypeptides include “polypeptide variants.” Polypeptide variants may differ from a naturally occurring polypeptide in one or more substitutions, deletions, additions and/or insertions. Such variants may be naturally occurring, e.g., a splice variant, or may be synthetically generated, for example, by modifying one or more of the above polypeptide sequences. For example, in particular embodiments, it may be desirable to improve the binding affinity and/or other biological properties of a polypeptide by introducing one or more substitutions, deletions, additions and/or insertions the polypeptide.
- polypeptides include polypeptides having at least about 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 86%, 97%, 98%, or 99% amino acid identity to any of the reference sequences contemplated herein, typically where the variant maintains at least one biological activity of the reference sequence.
- the biological activity is binding affinity.
- the biological activity is cytolytic activity.
- Polypeptide variants include biologically active “polypeptide fragments.”
- biologically active polypeptide fragments include anti-CD33 VHH domains, intracellular signaling domains, and the like.
- biologically active fragment or minimal biologically active fragment refers to a polypeptide fragment that retains at least 100%, at least 90%, at least 80%, at least 70%, at least 60%, at least 50%, at least 40%, at least 30%, at least 20%, at least 10%, or at least 5% of the naturally occurring polypeptide activity.
- a polypeptide fragment can comprise an amino acid chain at least 5 to about 1700 amino acids long.
- fragments are at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700 or more amino acids long.
- the polypeptides set forth herein may comprise one or more amino acids denoted as “X” or “Xaa,” which are used interchangeably.
- X if present in an amino acid SEQ ID NO, refers to any one or more amino acids.
- SEQ ID NOs denoting a fusion protein comprise a sequence of continuous X residues that cumulatively represent any amino acid sequence.
- XX represent any two amino acid combination.
- XX represents two serines, SS.
- “XX” represents any two amino acid combination that reduces immunogenicity.
- XX represents the amino acids KP.
- polypeptides may be altered in various ways including amino acid substitutions, deletions, truncations, and insertions. Methods for such manipulations are generally known in the art.
- amino acid sequence variants of a reference polypeptide can be prepared by mutations in the DNA. Methods for mutagenesis and nucleotide sequence alterations are well known in the art. See, for example, Kunkel (1985, Proc. Natl. Acad. Sci. USA. 82: 488-492), Kunkel etal., (1987 , Methods inEnzymol, 154: 367- 382), U.S. Pat. No. 4,873,192, Watson, J. D.
- a polypeptide variant comprises one or more conservative substitutions.
- a “conservative substitution” is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the polypeptide to be substantially unchanged. Modifications may be made in the structure of the polynucleotides and polypeptides contemplated in particular embodiments and still obtain a functional molecule that encodes a variant or derivative polypeptide with desirable characteristics.
- amino acid changes in the protein variants disclosed herein are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids.
- a conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains.
- Naturally occurring amino acids are generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In a peptide or protein, suitable conservative substitutions of amino acids are known to those of skill in this art and generally can be made without altering a biological activity of a resulting molecule.
- the polynucleotide sequences encoding them can be separated by an IRES sequence or a polynucleotide sequence encoding a ribosomal skip sequence as disclosed elsewhere herein.
- Polypeptides contemplated in particular embodiments include fusion polypeptides.
- fusion polypeptides and polynucleotides encoding fusion polypeptides are provided.
- Fusion polypeptides and fusion proteins refer to a polypeptide having at least two, three, four, five, six, seven, eight, nine, or ten polypeptide segments.
- a fusion polypeptide comprises one or more CD33 VHHDARIC components.
- the fusion polypeptide comprises one or more CD33 VHHDARICs.
- two or more CD33 VHH DARIC components and/or other polypeptides can be expressed as a fusion protein that comprises one or more self-cleaving peptide sequences between the polypeptides as disclosed elsewhere herein.
- a fusion polypeptide comprises a CD33 DARIC signaling component, a self-cleaving polypeptide sequence or ribosomal skip sequence, and a CD33 VHHDARIC binding component.
- a fusion polypeptide comprises a CD33 DARIC signaling component, a self-cleaving polypeptide sequence or ribosomal skip sequence, a CD33 VHH DARIC binding component, another self-cleaving polypeptide sequence or ribosomal skip sequence, and another DARIC binding component that is directed against another target antigen.
- Fusion polypeptides can comprise one or more polypeptide domains or segments including, but are not limited to signal peptides, cell permeable peptide domains (CPP), binding domains, signaling domains, etc., epitope tags (e.g., maltose binding protein (“MBP”), glutathione S transferase (GST), HIS6, MYC, FLAG, V5, VSV-G, and HA), polypeptide linkers, and polypeptide cleavage signals.
- Fusion polypeptides are typically linked C-terminus to N-terminus, although they can also be linked C-terminus to C-terminus, N-terminus to N- terminus, or N-terminus to C-terminus.
- the polypeptides of the fusion protein can be in any order. Fusion polypeptides or fusion proteins can also include conservatively modified variants, polymorphic variants, alleles, mutants, subsequences, and interspecies homologs, so long as the desired activity of the fusion polypeptide is preserved. Fusion polypeptides may be produced by chemical synthetic methods or by chemical linkage between the two moieties or may generally be prepared using other standard techniques. Ligated DNA sequences comprising the fusion polypeptide are operably linked to suitable transcriptional or translational control elements as disclosed elsewhere herein.
- Fusion polypeptides may optionally comprise one or more linkers that can be used to link the one or more polypeptides or domains within a polypeptide.
- a peptide linker sequence may be employed to separate any two or more polypeptide components by a distance sufficient to ensure that each polypeptide folds into its appropriate secondary and tertiary structures so as to allow the polypeptide domains to exert their desired functions.
- Such a peptide linker sequence is incorporated into the fusion polypeptide using standard techniques in the art.
- Suitable peptide linker sequences may be chosen based on the following factors: (1) their ability to adopt a flexible extended conformation; (2) their inability to adopt a secondary structure that could interact with functional epitopes on the first and second polypeptides; and (3) the lack of hydrophobic or charged residues that might react with the polypeptide functional epitopes.
- preferred peptide linker sequences contain Gly, Asn and Ser residues. Other near neutral amino acids, such as Thr and Ala may also be used in the linker sequence.
- Amino acid sequences which may be usefully employed as linkers include those disclosed in Maratea et al., Gene 40:39-46, 1985; Murphy et al., Proc. Natl. Acad. Sci.
- Linker sequences are not required when a particular fusion polypeptide segment contains non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric interference.
- preferred linkers are typically flexible amino acid subsequences which are synthesized as part of a recombinant fusion protein.
- Linker polypeptides can be between 1 and 200 amino acids in length, between 1 and 100 amino acids in length, or between 1 and 50 amino acids in length, including all integer values in between.
- Exemplary polypeptide cleavage signals include polypeptide cleavage recognition sites such as protease cleavage sites, nuclease cleavage sites e.g., rare restriction enzyme recognition sites, self-cleaving ribozyme recognition sites), and self-cleaving viral oligopeptides (see deFelipe and Ryan, 2004. Traffic, 5(8); 616-26).
- Suitable protease cleavages sites and self-cleaving peptides are known to the skilled person (.sue, e.g., in Ryan et al., 1997. Gener. Virol. 78, 699-722; Scymczak et al. (2004) Nature Biotech. 5, 589-594).
- Exemplary protease cleavage sites include, but are not limited to the cleavage sites of potyvirus NIa proteases (e.g., tobacco etch virus protease), potyvirus HC proteases, potyvirus Pl (P35) proteases, byovirus NIa proteases, byovirus RNA-2-encoded proteases, aphthovirus L proteases, enterovirus 2A proteases, rhinovirus 2A proteases, picoma 3C proteases, comovirus 24K proteases, nepovirus 24K proteases, RTSV (rice tungro spherical vims) 3 C-like protease, PYVF (parsnip yellow fleck vims) 3 C-like protease, heparin, thrombin, factor Xa and enterokinase.
- potyvirus NIa proteases e.g., tobacco etch virus protease
- TEV tobacco etch vims protease cleavage sites
- EXXYXQ(G/S) SEQ ID NO: 99
- ENLYFQG SEQ ID NO: 100
- ENLYFQS SEQ ID NO: 101
- X represents any amino acid (cleavage by TEV occurs between Q and G or Q and S).
- the polypeptide cleavage signal is a viral self-cleaving peptide or ribosomal skipping sequence.
- ribosomal skipping sequences include, but are not limited to: a 2A or 2A-like site, sequence or domain (Donnelly etal., 2001. J. Gen. Virol. 82:1027-1041).
- the viral 2A peptide is an aphthovirus 2A peptide, a potyvirus 2A peptide, or a cardiovims 2A peptide.
- the viral 2A peptide is selected from the group consisting of: a foot-and-mouth disease virus (FMDV) 2A peptide, an equine rhinitis A virus (ERAV) 2A peptide, a Thosea asigna virus (TaV) 2A peptide, a porcine teschovirus-1 (PTV-1) 2A peptide, a Theilovirus 2A peptide, and an encephalomyocarditis virus 2A peptide.
- FMDV foot-and-mouth disease virus
- EAV equine rhinitis A virus
- TaV Thosea asigna virus
- PTV-1 porcine teschovirus-1
- a polypeptide or fusion polypeptide comprises one or more CD33 VHH DARIC components, or CD33 VHH DARICs.
- a fusion polypeptide comprises a CD33 DARIC signaling component and a CD33 VHH DARIC binding component separated by a self-cleaving polypeptide sequence.
- a fusion polypeptide comprises the sequence set forth in any one of SEQ ID NOs: 22-63.
- polynucleotides encoding CD33 VHH DARICs, CD33 VHH DARIC binding components, CD33 DARIC signaling components and fragments thereof are provided.
- polynucleotide or “nucleic acid” refer to deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and DNA/RNA hybrids. Polynucleotides may be single-stranded or double-stranded and either recombinant, synthetic, or isolated.
- Polynucleotides include, but are not limited to: pre-messenger RNA (pre-mRNA), messenger RNA (mRNA), RNA, synthetic RNA, synthetic mRNA, genomic DNA (gDNA), PCR amplified DNA, complementary DNA (cDNA), synthetic DNA, or recombinant DNA.
- pre-mRNA pre-messenger RNA
- mRNA messenger RNA
- RNA synthetic RNA
- mRNA genomic DNA
- gDNA genomic DNA
- cDNA complementary DNA
- synthetic DNA or recombinant DNA.
- Polynucleotides refer to a polymeric form of nucleotides of at least 5, at least 10, at least 15, at least 20, at least 25, at least 30, at least 40, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500, at least 1000, at least 5000, at least 10000, or at least 15000 or more nucleotides in length, either ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide, as well as all intermediate lengths.
- intermediate lengths in this context, means any length between the quoted values, such as 6, 7, 8, 9, etc., 101, 102, 103, etc.,' 151, 152, 153, etc.,' 201, 202, 203, etc.
- polynucleotides or variants have at least or about 50%, 55%, 60%, 65%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a reference sequence.
- isolated polynucleotide refers to a polynucleotide that has been purified from the sequences which flank it in a naturally-occurring state, e.g., a DNA fragment that has been removed from the sequences that are normally adjacent to the fragment.
- an “isolated polynucleotide” also refers to a complementary DNA (cDNA), a recombinant DNA, or other polynucleotide that does not exist in nature and that has been made by the hand of man.
- an isolated polynucleotide is a synthetic polynucleotide, a semi-synthetic polynucleotide, or a polynucleotide obtained or derived from a recombinant source.
- a polynucleotide comprises an mRNA encoding a polypeptide contemplated herein.
- the mRNA comprises a cap, one or more nucleotides, and a poly(A) tail.
- polynucleotides encoding one or more CD33 VHH DARIC components may be codon-optimized.
- codon-optimized refers to substituting codons in a polynucleotide encoding a polypeptide in order to increase the expression, stability and/or activity of the polypeptide.
- Factors that influence codon optimization include, but are not limited to one or more of: (i) variation of codon biases between two or more organisms or genes or synthetically constmcted bias tables, (ii) variation in the degree of codon bias within an organism, gene, or set of genes, (iii) systematic variation of codons including context, (iv) variation of codons according to their decoding tRNAs, (v) variation of codons according to GC %, either overall or in one position of the triplet, (vi) variation in degree of similarity to a reference sequence for example a naturally occurring sequence, (vii) variation in the codon frequency cutoff, (viii) structural properties of mRNAs transcribed from the DNA sequence, (ix) prior knowledge about the function of the DNA sequences upon which design of the codon substitution set is to be based, (x) systematic variation of codon sets for each amino acid, and/or (xi) isolated removal of spurious translation initiation sites.
- nucleotide refers to a heterocyclic nitrogenous base in N- glycosidic linkage with a phosphorylated sugar. Nucleotides are understood to include natural bases, and a wide variety of art-recognized modified bases. Such bases are generally located at the 1 ' position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. In ribonucleic acid (RNA), the sugar is a ribose, and in deoxyribonucleic acid (DNA) the sugar is a deoxyribose, i.e., a sugar lacking a hydroxyl group that is present in ribose.
- RNA ribonucleic acid
- DNA deoxyribonucleic acid
- polynucleotides include, but are not limited to, polynucleotides encoding polypeptides set forth in SEQ ID NOs: 22-63.
- polynucleotides contemplated herein may be combined with other DNA sequences, such as promoters and/or enhancers, untranslated regions (UTRs), signal sequences, Kozak sequences, polyadenylation signals, additional restriction enzyme sites, multiple cloning sites, internal ribosomal entry sites (IRES), recombinase recognition sites (e.g., LoxP, FRT, and Att sites), termination codons, transcriptional termination signals, and polynucleotides encoding self-cleaving polypeptides, epitope tags, as disclosed elsewhere herein or as known in the art, such that their overall length may vary considerably. It is therefore contemplated that a polynucleotide fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use in the intended recombinant DNA protocol.
- Polynucleotides can be prepared, manipulated, expressed and/or delivered using any of a variety of well-established techniques known and available in the art.
- a nucleotide sequence encoding the polypeptide can be inserted into appropriate vector.
- vectors include, but are not limited to plasmid, autonomously replicating sequences, and transposable elements, e.g., Sleeping Beauty, PiggyBac.
- vectors include, without limitation, plasmids, phagemids, cosmids, artificial chromosomes such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or Pl -derived artificial chromosome (PAC), bacteriophages such as lambda phage or M13 phage, and animal viruses.
- artificial chromosomes such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or Pl -derived artificial chromosome (PAC)
- bacteriophages such as lambda phage or M13 phage
- animal viruses include, without limitation, plasmids, phagemids, cosmids, artificial chromosomes such as yeast artificial chromosome (YAC), bacterial artificial chromosome (BAC), or Pl -derived artificial chromosome (PAC), bacteriophages such as lambda phage or M13 phage, and animal viruses.
- viruses useful as vectors include, without limitation, retrovims (including lentivirus), adenovirus, adeno-associated virus, herpesvirus (e.g., herpes simplex virus), poxvirus, baculovirus, papillomavirus, and papovavirus (e.g., SV40).
- retrovims including lentivirus
- adenovirus e.g., adeno-associated virus
- herpesvirus e.g., herpes simplex virus
- poxvirus baculovirus
- papillomavirus papillomavirus
- papovavirus e.g., SV40
- expression vectors include, but are not limited to, pClneo vectors (Promega) for expression in mammalian cells; pLenti4/V5-DESTTM, pLenti6/V5- DESTTM, and pLenti6.2/V5-GW/lacZ (Invitrogen) for lentivirus-mediated gene transfer and expression in mammalian cells.
- coding sequences of polypeptides disclosed herein can be ligated into such expression vectors for the expression of the polypeptides in mammalian cells.
- the vector is an episomal vector or a vector that is maintained extrachromosomally.
- episomal vector refers to a vector that is able to replicate without integration into host’s chromosomal DNA and without gradual loss from a dividing host cell also meaning that said vector replicates extrachromosomally or episomally.
- “Expression control sequences,” “control elements,” or “regulatory sequences” present in an expression vector are those non-translated regions of the vector including an origin of replication, selection cassettes, promoters, enhancers, translation initiation signals (Shine Dalgamo sequence or Kozak sequence) introns, a polyadenylation sequence, 5' and 3' untranslated regions, all of which interact with host cellular proteins to carry out transcription and translation.
- Such elements may vary in their strength and specificity.
- any number of suitable transcription and translation elements including ubiquitous promoters and inducible promoters may be used.
- a polynucleotide comprises a vector, including but not limited to expression vectors and viral vectors.
- a vector may comprise one or more exogenous, endogenous, or heterologous control sequences such as promoters and/or enhancers.
- An “endogenous control sequence” is one which is naturally linked with a given gene in the genome.
- An “exogenous control sequence” is one which is placed in juxtaposition to a gene by means of genetic manipulation (i.e., molecular biological techniques) such that transcription of that gene is directed by the linked enhancer/promoter.
- a “heterologous control sequence” is an exogenous sequence that is from a different species than the cell being genetically manipulated.
- a “synthetic” control sequence may comprise elements of one more endogenous and/or exogenous sequences, and/or sequences determined in vitro or in silico that provide optimal promoter and/or enhancer activity for the particular therapy.
- promoter refers to a recognition site of a polynucleotide (DNA or RNA) to which an RNA polymerase binds. An RNA polymerase initiates and transcribes polynucleotides operably linked to the promoter.
- promoters operative in mammalian cells comprise an AT-rich region located approximately 25 to 30 bases upstream from the site where transcription is initiated and/or another sequence found 70 to 80 bases upstream from the start of transcription, a CNCAAT region where N may be any nucleotide.
- enhancer refers to a segment of DNA which contains sequences capable of providing enhanced transcription and in some instances can function independent of their orientation relative to another control sequence.
- An enhancer can function cooperatively or additively with promoters and/or other enhancer elements.
- promoter/enhancer refers to a segment of DNA which contains sequences capable of providing both promoter and enhancer functions.
- operably linked refers to a juxtaposition wherein the components described are in a relationship permitting them to function in their intended manner.
- the term refers to a functional linkage between a nucleic acid expression control sequence (such as a promoter, and/or enhancer) and a second polynucleotide sequence, e.g., a polynucleotide-of-interest, wherein the expression control sequence directs transcription of the nucleic acid corresponding to the second sequence.
- constitutive expression control sequence refers to a promoter, enhancer, or promoter/enhancer that continually or continuously allows for transcription of an operably linked sequence.
- a constitutive expression control sequence may be a “ubiquitous” promoter, enhancer, or promoter/enhancer that allows expression in a wide variety of cell and tissue types or a “cell specific,” “cell type specific,” “cell lineage specific,” or “tissue specific” promoter, enhancer, or promoter/enhancer that allows expression in a restricted variety of cell and tissue types, respectively.
- Illustrative ubiquitous expression control sequences suitable for use in particular embodiments include, but are not limited to, a cytomegalovirus (CMV) immediate early promoter, a viral simian virus 40 (SV40) e.g., early or late), a Moloney murine leukemia virus (MoMLV) LTR promoter, a Rous sarcoma virus (RSV) LTR, a herpes simplex virus (HSV) (thymidine kinase) promoter, H5, P7.5, and Pl 1 promoters from vaccinia virus, an elongation factor 1 -alpha (EFla) promoter, early growth response 1 (EGR1), ferritin H (FerH), ferritin L (FerL), Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), eukaryotic translation initiation factor 4A1 (EIF4A1), heat shock 70kDa protein 5 (HSPA5), heat shock protein 90kDa beta
- a vector comprises an MNDU3 promoter.
- a vector comprises an EFla promoter comprising the first intron of the human EFla gene.
- a vector comprises an EFla promoter that lacks the first intron of the human EFla gene.
- a cell, cell type, cell lineage or tissue specific expression control sequence may be desirable to use to achieve cell type specific, lineage specific, or tissue specific expression of a desired polynucleotide sequence (e g., to express a particular nucleic acid encoding a polypeptide in only a subset of cell types, cell lineages, or tissues or during specific stages of development).
- an “internal ribosome entry site” or “IRES” refers to an element that promotes direct internal ribosome entry to the initiation codon, such as ATG, of a cistron (a protein encoding region), thereby leading to the cap-independent translation of the gene. See, e.g., lackson etal, 1990. Trends Biochem Sci 15(12):477-83) and Jackson and Kaminski. 1995. RNA 1 (10):985- 1000. Examples of IRES generally employed by those of skill in the art include those described in U.S. Pat. No. 6,692,736.
- IRES immunoglobulin heavy-chain binding protein
- VEGF vascular endothelial growth factor
- FGF-2 fibroblast growth factor 2
- IGFII insulinlike growth factor
- EMCV encephelomy carditis virus
- the IRES used in polynucleotides contemplated herein is an EMCV IRES.
- the polynucleot ides a consensus Kozak sequence.
- Kozak sequence refers to a short nucleotide sequence that greatly facilitates the initial binding of mRNA to the small subunit of the ribosome and increases translation.
- the consensus Kozak sequence is (GCC)RCCATGG (SEQ ID NO: 124), where R is a purine (A or G) (Kozak, 1986. Cell. 44(2):283-92, and Kozak, 1987. Nucleic Acids Res. 15(20):8125- 48).
- vectors comprise a polyadenylation sequence 3' of a polynucleotide encoding a polypeptide to be expressed.
- polyA site or “polyA sequence” as used herein denotes a DNA sequence which directs both the termination and polyadenylation of the nascent RNA transcript by RNA polymerase n.
- Polyadenylation sequences can promote mRNA stability by addition of a polyA tail to the 3' end of the coding sequence and thus, contribute to increased translational efficiency.
- Cleavage and polyadenylation are directed by a poly(A) sequence in the RNA.
- the core poly(A) sequence for mammalian pre-mRNAs has two recognition elements flanking a cleavage-polyadenylation site. Typically, an almost invariant AAUAAA hexamer lies 20-50 nucleotides upstream of a more variable element rich in U or GU residues. Cleavage of the nascent transcript occurs between these two elements and is coupled to the addition of up to 250 adenosines to the 5' cleavage product.
- the core poly(A) sequence is an ideal polyA sequence (e.g, AATAAA, ATTAAA, AGTAAA).
- the poly(A) sequence is an SV40 polyA sequence, a bovine growth hormone polyA sequence (BGHpA), a rabbit [3-gIobin polyA sequence (rPgpA), variants thereof, or another suitable heterologous or endogenous polyA sequence known in the art.
- the poly(A) sequence is synthetic.
- polynucleotides encoding one or more polypeptides, or fusion polypeptides may be introduced into immune effector cells, e.g., T cells, by both non-viral and viral methods.
- delivery of one or more polynucleotides may be provided by the same method or by different methods, and/or by the same vector or by different vectors.
- vector is used herein to refer to a nucleic acid molecule capable transferring or transporting another nucleic acid molecule.
- the transferred nucleic acid is generally linked to, e.g., inserted into, the vector nucleic acid molecule.
- a vector may include sequences that direct autonomous replication in a cell, or may include sequences sufficient to allow integration into host cell DNA.
- non-viral vectors are used to deliver one or more polynucleotides contemplated herein to a T cell.
- non-viral vectors include, but are not limited to plasmids (e.g., DNA plasmids or RNA plasmids), transposons, cosmids, and bacterial artificial chromosomes.
- plasmids e.g., DNA plasmids or RNA plasmids
- transposons e.g., DNA plasmids or RNA plasmids
- cosmids e.g., cosmids, and bacterial artificial chromosomes.
- Illustrative methods of non-viral delivery of polynucleotides contemplated in particular embodiments include, but are not limited to: electroporation, sonoporation, lipofection, microinjection, biolistics, virosomes, liposomes, immunoliposomes, nanoparticles, polycation or lipidmucleic acid conjugates, naked DNA, artificial virions, DEAE-dextran-mediated transfer, gene gun, and heat-shock.
- polynucleotide delivery systems suitable for use in particular embodiments contemplated in particular embodiments include, but are not limited to those provided by Amaxa Biosystems, Maxcyte, Inc., BTX Molecular Delivery Systems, and Copernicus Therapeutics Inc.
- Lipofection reagents are sold commercially (e.g., TransfectamTM and LipofectinTM). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides have been described in the literature. See e.g., Liu el al. (2003) Gene Therapy. 10: 180-187; and Balazs etal. (2011) Journal of Drug Delivery. 2011 : 1-12.
- Antibody-targeted, bacterially derived, non-living nanocell-based delivery is also contemplated in particular embodiments.
- Viral vectors comprising polynucleotides contemplated in particular embodiments can be delivered in vivo by administration to an individual patient, typically by systemic administration e.g., intravenous, intraperitoneal, intramuscular, subdermal, or intracranial infusion) or topical application, as described below.
- vectors can be delivered to cells ex vivo, such as cells explanted from an individual patient ⁇ e.g., mobilized peripheral blood, lymphocytes, bone marrow aspirates, tissue biopsy, etc.) or universal donor hematopoietic stem cells, followed by reimplantation of the cells into a patient.
- viral vectors comprising polynucleotides contemplated herein are administered directly to an organism for transduction of cells in vivo.
- naked DNA can be administered.
- Administration is by any of the routes normally used for introducing a molecule into ultimate contact with blood or tissue cells including, but not limited to, injection, infusion, topical application and electroporation. Suitable methods of administering such nucleic acids are available and well known to those of skill in the art, and, although more than one route can be used to administer a particular composition, a particular route can often provide a more immediate and more effective reaction than another route.
- viral vector systems suitable for use in particular embodiments contemplated in particular embodiments include, but are not limited to, adeno- associated virus (AAV), retrovirus, herpes simplex virus, adenovirus, and vaccinia virus vectors.
- AAV adeno-associated virus
- retrovirus retrovirus
- herpes simplex virus adenovirus
- vaccinia virus vectors vaccinia virus vectors.
- one or more polynucleotides encoding one or more CD33 VHH DARIC components and/or other polypeptides contemplated herein are introduced into an immune effector cell, e.g., T cell, by transducing the cell with a recombinant adeno- associated virus (rAAV), comprising the one or more polynucleotides.
- rAAV adeno- associated virus
- one or more polynucleotides encoding one or more CD33 VHH DARIC components and/or other polypeptides contemplated herein are introduced into an immune effector cell, e.g., T cell, by transducing the cell with a retrovirus, e.g, lentivirus, comprising the one or more polynucleotides.
- an immune effector cell e.g., T cell
- a retrovirus e.g, lentivirus
- retrovirus refers to an RNA virus that reverse transcribes its genomic RNA into a linear double-stranded DNA copy and subsequently covalently integrates its genomic DNA into a host genome.
- retroviruses suitable for use in particular embodiments include, but are not limited to: Moloney murine leukemia virus (M- MuLV), Moloney murine sarcoma virus (MoMSV), Harvey murine sarcoma virus (HaMuSV), murine mammary tumor virus (MuMTV), gibbon ape leukemia virus (GaLV), feline leukemia virus (FLV), spumavirus, Friend murine leukemia virus, Murine Stem Cell Virus (MSCV) and Rous Sarcoma Virus (RSV)) and lentivirus.
- M- MuLV Moloney murine leukemia virus
- MoMSV Moloney murine sarcoma virus
- Harvey murine sarcoma virus HaMuSV
- murine mammary tumor virus Mu
- lentivirus refers to a group (or genus) of complex retroviruses.
- Illustrative lentiviruses include, but are not limited to, HIV (human immunodeficiency virus; including HIV type 1, and HIV type 2); visna-maedi virus (VMV) virus; the caprine arthritis-encephalitis virus (CAEV); equine infectious anemia virus (EIAV); feline immunodeficiency virus (FIV); bovine immune deficiency virus (BIV); and simian immunodeficiency virus (SIV).
- HIV based vector backbones i.e., HIV cis-acting sequence elements
- HIV cis-acting sequence elements are preferred.
- a lentiviral vector contemplated herein comprises one or more LTRs, and one or more, or all, of the following accessory elements: a cPPT/FLAP, a Psi ( ) packaging signal, an export element, poly (A) sequences, and may optionally comprise a WPRE or HPRE, an insulator element, a selectable marker, and a cell suicide gene, as discussed elsewhere herein.
- lentiviral vectors are produced according to known methods. See e.g., Kutner etal, BMC Biotechnol. 2009;9:10. doi: 10.1186/1472-6750-9-10; Kutnere/tz/. Nat. Protoc. 2009;4(4):495-505. doi: 10.1038/nprot.2009.22.
- one or more polynucleotides encoding one or more CD33 VHH DARIC components and/or other polypeptides contemplated herein are introduced into an immune effector cell, by transducing the cell with an adenovirus comprising the one or more polynucleotides.
- one or more polynucleotides encoding one or more CD33 VHH DARIC components and/or other polypeptides contemplated herein are introduced into an immune effector cell by transducing the cell with a herpes simplex virus, e.g., HSV-1, HSV- 2, comprising the one or more polynucleotides.
- HSV-based vectors are described in, for example, U.S. Pat. Nos. 5,837,532, 5,846,782, and 5,804,413, and International Patent Applications WO 91/02788, WO 96/04394, WO 98/15637, and WO 99/06583, each of which are incorporated by reference herein in its entirety.
- cells are modified to express a CD33 VHH DARIC and one or more CD33 VHH DARIC components, and/or fusion proteins contemplated herein, for use in the treatment of cancer.
- Cells may be non-genetically modified to express one or more of the polypeptides contemplated herein, or in particular preferred embodiments, cells may be genetically modified to express one or more of the polypeptides contemplated herein.
- the term “genetically engineered” or “genetically modified” refers to the addition of extra genetic material in the form of DNA or RNA into the total genetic material in a cell.
- the terms, “genetically modified cells,” “modified cells,” and “redirected cells,” are used interchangeably in particular embodiments.
- one or more CD33 VHH DARIC components contemplated herein are introduced and expressed in immune effector cells to improve the efficacy of the immune effector cells.
- an “immune effector cell,” is any cell of the immune system that has one or more effector functions (e.g, cytotoxic cell killing activity, secretion of cytokines, induction of ADCC and/or CDC).
- the illustrative immune effector cells contemplated herein are T lymphocytes, including but not limited to cytotoxic T cells (CTLs; CD8 + T cells), TILs, and helper T cells (HTLs; CD4 + T cells).
- the cells comprise a
- the cells comprise y6 T cells.
- immune effector cells include natural killer (NK) cells.
- immune effector cells include natural killer T (NKT) cells.
- Immune effector cells can be autologous/autogeneic (“self’) or non-autologous (“non-self,” e.g., allogeneic, syngeneic or xenogeneic).
- “Autologous,” as used herein, refers to cells from the same subject. “Allogeneic,” as used herein, refers to cells of the same species that differ genetically to the cell in comparison. “Syngeneic,” as used herein, refers to cells of a different subject that are genetically identical to the cell in comparison. “Xenogeneic,” as used herein, refers to cells of a different species to the cell in comparison. In preferred embodiments, the cells are human autologous immune effector cells.
- T lymphocytes suitable for introducing one or more CD33 VHH DARIC components contemplated herein include T lymphocytes.
- T cell or “T lymphocyte” are art-recognized and are intended to include thymocytes, immature T lymphocytes, mature T lymphocytes, resting T lymphocytes, or activated T lymphocytes.
- a T cell can be a T helper (Th) cell, for example a T helper 1 (Thl) or a T helper 2 (Th2) cell.
- Th T helper
- the T cell can be a helper T cell (HTL; CD4 + T cell), a cytotoxic T cell (CTL; CD8 + T cell), CD4 + CD8 + T cell, CD4 CD8" T cell, or any other subset of T cells.
- the T cell expresses a T cell receptor.
- T cell receptors comprise two subunits, an alpha chain and a beta chain subunit (a0TCR), or a gamma chain and a delta chain subunit y8TCR), each of which is a unique protein produced by recombination event in each T cell’s genome.
- a T cell is an a
- a T cell is a ySTCR T cell T cell).
- Other illustrative populations of T cells suitable for use in particular embodiments include naive T cells and memory T cells.
- immune effector cells comprising one or more CD33 VHH DARIC components contemplated herein.
- immune effector cells also include NK cells, NKT cells, neutrophils, and macrophages.
- Immune effector cells also include progenitors of effector cells wherein such progenitor cells can be induced to differentiate into immune effector cells in vivo or in vitro.
- immune effector cells include progenitors of immune effectors cells such as hematopoietic stem cells (HSCs) contained within the CD34 + population of cells derived from cord blood, bone marrow or mobilized peripheral blood which upon administration in a subject differentiate into mature immune effector cells, or which can be induced in vitro to differentiate into mature immune effector cells.
- HSCs hematopoietic stem cells
- CD34 + cell refers to a cell expressing the CD34 protein on its cell surface.
- CD34 refers to a cell surface glycoprotein (e.g., sialomucin protein) that often acts as a cell-cell adhesion factor and is involved in T cell entrance into lymph nodes.
- the CD34 + cell population contains hematopoietic stem cells (HSC), which upon administration to a patient differentiate and contribute to all hematopoietic lineages, including T cells, NK cells, NKT cells, neutrophils and cells of the monocyte/macrophage lineage.
- HSC hematopoietic stem cells
- the method comprises transfecting or transducing immune effector cells isolated from an individual such that the immune effector cells with one or more nucleic acids and/or vectors, e.g., a lentiviral vector comprising a nucleic acid encoding one or more CD33 VHH DARIC components contemplated herein.
- the method comprises transfecting or transducing immune effector cells isolated from an individual such that the immune effector cells express one or more CD33 VHH DARIC components contemplated herein.
- the immune effector cells are isolated from an individual and genetically modified without further manipulation in vitro.
- the immune effector cells are first activated and stimulated to proliferate in vitro prior to being genetically modified.
- the immune effector cells may be cultured before and/or after being genetically modified.
- the source of cells prior to in vitro manipulation or genetic modification of the immune effector cells described herein, the source of cells is obtained from a subject.
- the modified immune effector cells comprise T cells.
- T cells can be obtained from a number of sources including, but not limited to, peripheral blood mononuclear cells, bone marrow, lymph nodes tissue, cord blood, thymus issue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
- T cells can be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled person, such as sedimentation, e.g., FICOLLTM separation.
- an isolated or purified population of T cells is used.
- both cytotoxic and helper T lymphocytes can be sorted into naive, memory, and effector T cell subpopulations either before or after activation, expansion, and/or genetic modification.
- an isolated or purified population of T cells expresses one or more of the markers including, but not limited to a CD3 + , CD4 + , CD8 + , or a combination thereof.
- the T cells are isolated from an individual and first activated and stimulated to proliferate in vitro prior to being modified to express one or more CD33 VHH DARIC components
- T cells are often subjected to one or more rounds of stimulation, activation and/or expansion.
- T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 5,883,223; 6,905,874; 6,797,514; and 6,867,041, each of which is incorporated herein by reference in its entirety.
- T cells are activated and expanded for about 6 hours, about 12 hours, about 18 hours or about 24 hours prior to introduction of vectors or polynucleotides encoding one or more CD33 VHH DARIC components contemplated herein.
- compositions contemplated herein may comprise one or more CD33 VHH DARIC components, polynucleotides encoding one or more CD33 VHH DARIC components, vectors comprising same, genetically modified immune effector cells, bridging factors, etc.
- Compositions include, but are not limited to, pharmaceutical compositions.
- a “pharmaceutical composition” refers to a composition formulated in pharmaceutically-acceptable or physiologically-acceptable solutions for administration to a cell or an animal, either alone, or in combination with one or more other modalities of therapy.
- compositions may be administered in combination with other agents as well, such as, e.g., cytokines, growth factors, hormones, small molecules, chemotherapeutics, pro-drugs, drugs, antibodies, or other various pharmaceutically-active agents.
- agents such as, e.g., cytokines, growth factors, hormones, small molecules, chemotherapeutics, pro-drugs, drugs, antibodies, or other various pharmaceutically-active agents.
- agents e.g., cytokines, growth factors, hormones, small molecules, chemotherapeutics, pro-drugs, drugs, antibodies, or other various pharmaceutically-active agents.
- additional agents do not adversely affect the ability of the composition to deliver the intended therapy.
- phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient, or vehicle with which the bridging factors, polypeptides, polynucleotides, vectors comprising same, or genetically modified immune effector cells are administered.
- pharmaceutical carriers can be sterile liquids, such as cell culture media, water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
- Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- a composition comprising a pharmaceutically acceptable carrier is suitable for administration to a subject.
- a composition comprising a carrier is suitable for parenteral administration, e.g., intravascular (intravenous or intraarterial), intraperitoneal or intramuscular administration.
- a composition comprising a pharmaceutically acceptable carrier is suitable for intraventricular, intraspinal, or intrathecal administration.
- Pharmaceutically acceptable carriers include sterile aqueous solutions, cell culture media, or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the bridging factors, polypeptides, polynucleotides, vectors comprising same, or genetically modified immune effector cells, use thereof in the pharmaceutical compositions is contemplated.
- compositions contemplated herein comprise genetically modified T cells and a pharmaceutically acceptable carrier.
- a composition comprising a cell-based composition contemplated herein can be administered separately by enteral or parenteral administration methods or in combination with other suitable compounds to effect the desired treatment goals.
- compositions contemplated herein comprise a bridging factor and a pharmaceutically acceptable carrier.
- the pharmaceutically acceptable carrier must be of sufficiently high purity and of sufficiently low toxicity to render it suitable for administration to the human subject being treated. It further should maintain or increase the stability of the composition.
- the pharmaceutically acceptable carrier can be liquid or solid and is selected, with the planned manner of administration in mind, to provide for the desired bulk, consistency, etc., when combined with other components of the composition.
- the pharmaceutically acceptable carrier can be, without limitation, a binding agent e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.), a filler ⁇ e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates, calcium hydrogen phosphate, etc.), a lubricant (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.), a disintegrant (e.g., starch, sodium starch glycolate, etc.), or a wetting agent (e.g., sodium lauryl sulfate, etc.).
- a binding agent e.g., pregelatinized maize starch,
- compositions contemplated herein include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatins, amyloses, magnesium stearates, talcs, silicic acids, viscous paraffins, hydroxymethylcelluloses, polyvinylpyrrolidones and the like.
- buffers refers to a solution or liquid whose chemical makeup neutralizes acids or bases without a significant change in pH.
- buffers contemplated herein include, but are not limited to, Dulbecco's phosphate buffered saline (PBS), Ringer's solution, 5% dextrose in water (D5W), normal/physiologic saline (0.9% NaCl).
- the pharmaceutically acceptable carriers may be present in amounts sufficient to maintain a pH of the composition of about 7.
- the composition has a pH in a range from about 6.8 to about 7.4, e.g., 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, and 7.4.
- the composition has a pH of about 7.4.
- compositions contemplated herein may comprise a nontoxic pharmaceutically acceptable medium.
- the compositions may be a suspension.
- the term “suspension” as used herein refers to non-adherent conditions in which cells are not attached to a solid support. For example, cells maintained as a suspension may be stirred or agitated and are not adhered to a support, such as a culture dish.
- compositions contemplated herein are formulated in a suspension, where the modified T cells are dispersed within an acceptable liquid medium or solution, e.g., saline or serum-free medium, in an intravenous (IV) bag or the like.
- Acceptable diluents include, but are not limited to water, PlasmaLyte, Ringer's solution, isotonic sodium chloride (saline) solution, serum-free cell culture medium, and medium suitable for cryogenic storage, e.g., Cryostor® medium.
- a pharmaceutically acceptable carrier is substantially free of natural proteins of human or animal origin, and suitable for storing a composition comprising a population of modified T cells.
- the therapeutic composition is intended to be administered into a human patient, and thus is substantially free of cell culture components such as bovine serum albumin, horse serum, and fetal bovine serum.
- compositions are formulated in a pharmaceutically acceptable cell culture medium. Such compositions are suitable for administration to human subjects.
- the pharmaceutically acceptable cell culture medium is a serum free medium.
- Serum-free medium has several advantages over serum containing medium, including a simplified and better-defined composition, a reduced degree of contaminants, elimination of a potential source of infectious agents, and lower cost.
- the serum-free medium is animal-free, and may optionally be protein-free.
- the medium may contain biopharmaceutically acceptable recombinant proteins.
- “Animal-free” medium refers to medium wherein the components are derived from non-animal sources. Recombinant proteins replace native animal proteins in animal- free medium and the nutrients are obtained from synthetic, plant or microbial sources.
- Protein-free in contrast, is defined as substantially free of protein.
- serum-free media used in particular compositions includes, but is not limited to, QBSF-60 (Quality Biological, Inc ), StemPro-34 (Life Technologies), and X-VIVO 10.
- compositions comprising modified T cells are formulated in PlasmaLyte.
- compositions comprising modified T cells are formulated in a cryopreservation medium.
- cry opreservation media with cryopreservation agents may be used to maintain a high cell viability outcome post-thaw.
- cry opreservation media used in particular compositions includes, but is not limited to, CryoStor CS10, CryoStor CS5, and CryoStor CS2.
- the compositions are formulated in a solution comprising 50:50 PlasmaLyte A to CryoStor CS10.
- the composition is substantially free of mycoplasma, endotoxin, and microbial contamination.
- substantially free with respect to endotoxin is meant that there is less endotoxin per dose of cells than is allowed by the FDA for a biologic, which is a total endotoxin of 5 EU/kg body weight per day, which for an average 70 kg person is 350 EU per total dose of cells.
- compositions contemplated herein contain about 0.5 EU/ml to about 5.0 EU/ml, or about 0.5 EU/ml, 1.0 EU/ml, 1.5 EU/ml, 2.0 EU/ml, 2.5 EU/ml, 3.0 EU/ml, 3.5 EU/ml, 4.0 EU/ml, 4.5 EU/ml, or 5.0 EU/ml.
- formulation of pharmaceutically-acceptable carrier solutions is well-known to those of skill in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens, including e.g., enteral and parenteral, e.g, intravascular, intravenous, intrarterial, intraosseously, intraventricular, intracerebral, intracranial, intraspinal, intrathecal, and intramedullary administration and formulation.
- enteral and parenteral e.g, intravascular, intravenous, intrarterial, intraosseously, intraventricular, intracerebral, intracranial, intraspinal, intrathecal, and intramedullary administration and formulation.
- enteral and parenteral e.g, intravascular, intravenous, intrarterial, intraosseously, intraventricular, intracerebral, intracranial, intraspinal, intrathecal, and intramedullary administration and formulation.
- particular embodiments contemplated herein may comprise other
- compositions comprise an amount of immune effector cells comprising a polynucleotide encoding one or more CD33 VHH DARJC components contemplated herein.
- compositions comprise an amount of immune effector cells that express one or more CD33 VHHDARJC components contemplated herein.
- the term “amount” refers to “an amount effective” or “an effective amount” of cells comprising one or more CD33 VHH DARJC components contemplated herein, etc., to achieve a beneficial or desired prophylactic or therapeutic result in the presence of a bridging factor, including clinical results.
- a “prophylactically effective amount” refers to an amount of cells comprising one or more CD33 VHH DARIC components contemplated herein, etc., effective to achieve the desired prophylactic result in the presence of a bridging factor. Typically but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount is less than the therapeutically effective amount.
- a “therapeutically effective amount” refers to an amount of cells comprising one or more CD33 VHHDARIC components contemplated herein that is effective to “treat” a subject (e.g, a patient) in the presence of a bridging factor.
- a therapeutic amount is indicated, the precise amount of the compositions to be administered, cells, bridging factor, etc, can be determined by a physician with consideration of individual differences in age, weight, tumor size, extent of infection or metastasis, and condition of the patient (subject).
- a pharmaceutical composition comprising the immune effector cells described herein may be administered at a dosage of 10 2 to IO 10 cells/kg body weight, preferably 10 5 to 10 6 cells/kg body weight, including all integer values within those ranges.
- the number of cells will depend upon the ultimate use for which the composition is intended as will the type of cells included therein.
- the cells are generally in a volume of a liter or less, can be 500 mis or less, even 250 mis or 100 mis or less.
- the density of the desired cells is typically greater than 10 6 cells/ml and generally is greater than 10 7 cells/ml, generally 10 8 cells/ml or greater.
- the clinically relevant number of immune cells can be apportioned into multiple infusions that cumulatively equal or exceed 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , or 10 12 cells.
- lower numbers of cells in the range of 10 6 /kilogram ( 10 6 - 10 11 per patient) may be administered.
- the treatment may also include administration of mitogens (e.g, PHA) or lymphokines, cytokines, and/or chemokines (e.g., IFN-y, IL-2, IL-12, TNF-alpha, IL-18, and TNF-beta, GM-CSF, IL-4, IL-13, Flt3-L, RANTES, MIPla, etc.) as described herein to enhance induction of the immune response.
- mitogens e.g, PHA
- lymphokines e.g, lymphokines, cytokines, and/or chemokines (e.g., IFN-y, IL-2, IL-12, TNF-alpha, IL-18, and TNF-beta, GM-CSF, IL-4, IL-13, Flt3-L, RANTES, MIPla, etc.) as described herein to enhance induction of the immune response.
- chemokines e.g., IFN-y, IL
- compositions comprising the cells activated and expanded as described herein may be utilized in the treatment and prevention of diseases that arise in individuals who are immunocompromised.
- compositions contemplated herein are used in the treatment of cancer.
- the immune effector cells may be administered either alone, or as a pharmaceutical composition in combination with carriers, diluents, excipients, and/or with other components such as IL -2 or other cytokines or cell populations.
- compositions comprise an amount of genetically modified T cells, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
- compositions comprise an amount of bridging factor, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients.
- compositions comprise an effective amount of immune effector cells comprising one or more CD33 VHHDARIC components contemplated herein, alone or in combination with a bridging factor and/or one or more therapeutic agents, such as radiation therapy, chemotherapy, transplantation, immunotherapy, hormone therapy, photodynamic therapy, etc.
- therapeutic agents such as radiation therapy, chemotherapy, transplantation, immunotherapy, hormone therapy, photodynamic therapy, etc.
- the compositions may also be administered in combination with antibiotics.
- therapeutic agents may be accepted in the art as a standard treatment for a particular disease state as described herein, such as a particular cancer.
- Exemplary therapeutic agents contemplated include cytokines, growth factors, steroids, NSAIDs, DMARDs, anti-inflammatories, chemotherapeutics, radiotherapeutics, therapeutic antibodies, or other active and ancillary agents.
- a composition comprising an effective amount of immune effector cells comprising a polynucleotide encoding one or more CD33 VHH DARIC components contemplated herein is administered to a subject, and a composition comprising an effective amount of a bridging factor is administered to the subject, before, during, in combination with or subsequently to the cellular composition, and optionally repetitively administered to the subject.
- compositions comprising immune effector cells comprising a polynucleotide encoding one or more CD33 VHH DARIC components contemplated herein may be administered in conjunction with any number of antiinflammatory agents, chemotherapeutic agents, or therapeutic antibodies, and the like.
- Immune effector cells modified to express a polynucleotide encoding one or more CD33 VHHDARIC components contemplated herein provide improved methods of adoptive immunotherapy for use in the prevention, treatment, and amelioration of, or for preventing, treating, or ameliorating at least one symptom associated with an immune disorder, e.g., cancer.
- Immune effector cells comprising a CD33 DARIC signaling component, or a CD33 VHH DARIC binding component provide improved methods of adoptive immunotherapy for use in the prevention, treatment, and amelioration of, or for preventing, treating, or ameliorating at least one symptom associated with an immune disorder, e.g., cancer.
- immune effector cells modified to express a CD33 VHH DARIC provide improved methods of adoptive immunotherapy to fine-tune the safety and efficacy of a cytotoxic response against target cells, e.g., tumor cells, expressing target antigens while decreasing the risk of on-target antigen, off-target cell cytotoxicity (recognizing the target antigen on a normal, non-target cell).
- target cells e.g., tumor cells, expressing target antigens while decreasing the risk of on-target antigen, off-target cell cytotoxicity (recognizing the target antigen on a normal, non-target cell).
- a method of preventing, treating, or ameliorating at least one symptom of a cancer comprises administering the subject an effective amount of modified immune effector cells or T cells comprising one or more components of a CD33 VHH DARIC to redirect the cells to a target cell.
- the genetically modified cells are a more efficacious and safe cellular immunotherapy by virtue of transducing a chemically regulatable immunostimulatory signal.
- one or more immune effector cells are modified to express both a CD33 VHH DARIC binding component and a CD33 DARIC signaling component.
- the modified cells are administered to a subject in need thereof and home to the target cells via the interaction of the CD33 VHH binding component expressed on the immune effector cell and CD33 expressed on the target cell.
- a bridging factor is administered to the subject before the modified cells, about the same time as the modified cells, or after the modified cells have been administered to the subject.
- a ternary complex forms between the CD33 VHH DARIC binding component, the bridging factor, and the CD33 DARIC signaling component.
- the CD33 VHH DARIC transduces an immunostimulatory signal to the immune effector cell that in turn, elicits a cytotoxic response from the immune effector cell against the target cell.
- one or more immune effector cells are modified to express a CD33 DARIC signaling component.
- the modified cells are administered to a subject in need thereof.
- a CD33 VHH DARIC binding component can be administered to the subject before the modified cells, about the same time as the modified cells, or after the modified cells have been administered to the subject.
- the CD33 VHH DARIC binding component can be administered to the subject in a preformed complex with the bridging factor; at the same time as the bridging factor, but in a separate composition; or at a different time than the bridging factor.
- the CD33 VHH binding component binds CD33 expressed on the target cell, either in the presence or absence of the bridging factor.
- a ternary complex forms between the CD33 VHH DARIC binding component, the bridging factor, and the CD33 DARIC signaling component.
- the CD33 VHH DARIC transduces an immunostimulatory signal to the immune effector cell that in turn, elicits a cytotoxic response from the immune effector cell against the target cell.
- one or more immune effector cells are modified to express the CD33 DARIC signaling component.
- the modified cells are administered to a subject in need thereof.
- a CD33 VHH DARIC binding component can be administered to the subject before the modified cells, about the same time as the modified cells, or after the modified cells have been administered to the subject.
- the CD33 VHH DARIC binding component can be administered to the subject in a preformed complex with the bridging factor; at the same time as the bridging factor, but in a separate composition; or at a different time than the bridging factor.
- the CD33 binding component binds the target antigen expressed on the target cell, either in the presence or absence of the bridging factor.
- a ternary complex forms between the CD33 VHH DARIC binding component, the bridging factor, and the CD33 DARIC signaling component.
- the CD33 VHH DARIC transduces an immunostimulatory signal to the immune effector cell that in turn, elicits a cytotoxic response from the immune effector cell against the target cell.
- CD33 VHH DARIC activation can be induced in cases where remission or regression is incomplete and the condition relapses or becomes refractory to treatment.
- the specificity of a primary T cell is redirected to tumor or cancer cells that express CD33 by genetically modifying a T cell, e.g, a primary T cell, with one or more CD33 VHH DARIC components.
- the specificity of a primary T cell is redirected to tumor or cancer cells that express CD33 by genetically modifying a T cell, e.g., a primary T cell, with an engineered antigen receptor directed to the target antigen and one or more CD33 VHH DARIC components.
- the modified immune effector cells contemplated herein are used in the treatment of solid tumors or cancers.
- the modified immune effector cells contemplated herein are used in the treatment of solid tumors or cancers including, but not limited to: adrenal cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain/CNS cancer, breast cancer, bronchial tumors, cardiac tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chordoma, colon cancer, colorectal cancer, craniopharyngioma, ductal carcinoma in situ (DCIS) endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing’s sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fallopian tube cancer, fibrous histiosarcoma, fibrosarcom
- the modified immune effector cells contemplated herein are used in the treatment of solid tumors or cancers including, without limitation, non-small cell lung carcinoma, head and neck squamous cell carcinoma, colorectal cancer, pancreatic cancer, breast cancer, thyroid cancer, bladder cancer, cervical cancer, esophageal cancer, ovarian cancer, gastric cancer endometrial cancer, gliomas, glioblastomas, and oligodendroglioma.
- the modified immune effector cells contemplated herein are used in the treatment of solid tumors or cancers including, without limitation, non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer.
- the modified immune effector cells contemplated herein are used in the treatment of glioblastoma.
- the modified immune effector cells contemplated herein are used in the treatment of liquid cancers or hematological cancers.
- the modified immune effector cells contemplated herein are used in the treatment of B-cell malignancies, including but not limited to: leukemias, lymphomas, and multiple myeloma.
- the modified immune effector cells contemplated herein are used in the treatment of liquid cancers including, but not limited to leukemias, lymphomas, and multiple myelomas: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, hairy cell leukemia (HCL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML) and polycythemia vera, Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma, Burkitt lymphoma, small lymphocytic lymphoma (SLL), diffuse large B-cell lymphoma, follicular lymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblastic lymph
- ALL acute
- the modified immune effector cells contemplated herein are used in the treatment of acute myeloid leukemia (AML).
- AML acute myeloid leukemia
- Preferred cells for use in the methods contemplated herein include autologous/autogeneic (“self’) cells, preferably hematopoietic cells, more preferably T cells, and more preferably immune effector cells.
- self autologous/autogeneic
- a method comprises administering a therapeutically effective amount of modified immune effector cells that express one or more CD33 VHH DARIC components, to a patient in need thereof, and also administering a bridging factor to the subject.
- the cells are used in the treatment of patients at risk for developing an immune disorder.
- particular embodiments comprise the treatment or prevention or amelioration of at least one symptom of an immune disorder, e.g, cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of the modified immune effector cells contemplated herein and a bridging factor.
- a method comprises administering a therapeutically effective amount of modified immune effector cells that express a CD33 DARIC signaling component or a composition comprising the same, to a patient in need thereof, and also administering a CD33 VHH DARIC binding component and a bridging factor, optionally wherein the CD33 VHH DARIC binding component is bound to the bridging factor prior to administration, to the subject.
- the cells are used in the treatment of patients at risk for developing an immune disorder.
- particular embodiments comprise the treatment or prevention or amelioration of at least one symptom of an immune disorder, e.g., cancer, comprising administering to a subject in need thereof, a therapeutically effective amount of the modified immune effector cells that express a CD33 DARIC signaling component and optionally and engineered antigen receptor or another DARIC binding component, a CD33 VHH DARIC binding component, and a bridging factor.
- an immune disorder e.g., cancer
- modified immune effector cells CD33 DARIC VHH binding components, and/or bridging factor
- the quantity and frequency of administration of modified immune effector cells, CD33 DARIC VHH binding components, and/or bridging factor will be determined by such factors as the condition of the patient, and the type and severity of the patient's disease, although appropriate dosages and dose schedules may be determined by clinical trials.
- the effective amount of modified immune effector cells provided to a subject is at least 2 x 10 6 cells/kg, at least 3 x 10 6 cells/kg, at least 4 x 10 6 cells/kg, at least 5 x 10 6 cells/kg, at least 6 x 10 6 cells/kg, at least 7 x 10 6 cells/kg, at least 8 x 10 6 cells/kg, at least 9 x 10 6 cells/kg, or at least 10 x 10 6 cells/kg, or more cells/kg, including all intervening doses of cells.
- the effective amount of modified immune effector cells provided to a subject is about 2 x 10 6 cells/kg, about 3 x 10 6 cells/kg, about 4 x 10 6 cells/kg, about 5 x 10 6 cells/kg, about 6 x 10 6 cells/kg, about 7 x 10 6 cells/kg, about 8 x 10 6 cells/kg, about 9 x 10 6 cells/kg, or about 10 x 10 6 cells/kg, or more cells/kg, including all intervening doses of cells.
- the effective amount of modified immune effector cells provided to a subject is from about 2 x 10 6 cells/kg to about 10 x 10 6 cells/kg, about 3 x 10 6 cells/kg to about 10 x 10 6 cells/kg, about 4 x 10 6 cells/kg to about 10 x 10 6 cells/kg, about 5 x 10 6 cells/kg to about 10 x 10 6 cells/kg, 2 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 2 x 10 6 cells/kg to about 7 x 10 6 cells/kg, 2 x 10 6 cells/kg to about 8 x 10 6 cells/kg, 3 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 3 x 10 6 cells/kg to about 7 x 10 6 cells/kg, 3 x 10 6 cells/kg to about 8 x 10 6 cells/kg, 4 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 4 x 10 6 cells/kg to about 6 x 10 6 cells/kg, 4 x 10 6 cells
- compositions contemplated in particular embodiments may be required to effect the desired therapy.
- a composition may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times over a span of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5, years, 10 years, or more.
- Modified immune effector cells, CD33 VHH DARIC components, and bridging factor may be administered in the same or different compositions; in one or more compositions at the same time; or more than one composition at different times.
- Modified immune effector cells, CD33 VHH DARIC components, and bridging factor may be administered through the same route of administration or different routes.
- T cells can be activated from blood draws of from lOcc to 400cc.
- T cells are activated from blood draws of 20cc, 30cc, 40cc, 50cc, 60cc, 70cc, 80cc, 90cc, lOOcc, 150cc, 200cc, 250cc, 300cc, 350cc, or 400cc or more.
- using this multiple blood draw/multiple reinfusion protocol may serve to select out certain populations of T cells.
- a method of treating a subject diagnosed with a cancer comprises removing immune effector cells from the subject, modifying the immune effector cells by introducing one or more vectors encoding one or more CD33 VHH DARIC components into the cell and producing a population of modified immune effector cells, and administering the population of modified immune effector cells to the same subject.
- the immune effector cells comprise T cells.
- the methods for administering the cell compositions contemplated in particular embodiments include any method which is effective to result in reintroduction of ex vivo modified immune effector cells or reintroduction of modified progenitors of immune effector cells that upon introduction into a subject differentiate into mature immune effector cells.
- One method comprises modifying peripheral blood T cells ex vzvoby introducing one or more vectors encoding one or more CD33 VHH DARIC components into the cell and returning the transduced cells into the subject.
- CD33 DARICS CONTAINING A SECOND CO-STIMULATORY DOMAIN RESPOND TO CD33 + TUMOR CELLS
- CD33 VHH DARIC binding and signaling components were designed, constructed, and verified.
- CD33 VHH DARIC lentiviral vectors were constructed comprising an MNDU3 promoter operably linked to a polynucleotide encoding: a DARIC signaling component (CD8a-signal peptide, an FRB variant (T82L), a CD8a transmembrane domain, an intracellular 4-1BB co-stimulatory domain, and a CD3 zeta signaling domain); a P2A sequence; and a DARIC binding component (an IgK-signal peptide, an anti-CD33 VHH, a G4S linker, an FKBP12 domain, and various combination of transmembrane domain with an intracellular signaling domain ( Figure 1A).
- a DARIC signaling component CD8a-signal peptide, an FRB variant (T82L), a CD8a transmembrane domain, an intracellular 4-1BB co-stimulatory domain
- Untransduced T cells T cells transduced with empty vector and CD33 VHH DARIC T cells lacking the co-stimulatory domain linked to the FKBP12 portion were used as controls.
- T cells from three donors were each transduced with LVVs encoding CD33 VHH DARICs comprising a DARIC binding component containing co-stimulatory domains or the parental CD33 VHH DARIC control and expanded for 10 days. All samples, including untransduced T cells and T cells transduced with empty vector, were stained with recombinant CD33-Fc reagent. While untransduced and empty vector T cells did not bind the staining reagent, T cells transduced with a control CD33 DARIC and CD33 DARICs comprising a binding component that comprises a co-stimulatory domain were positively stained with the CD33-Fc staining ( Figure IB).
- the untransduced T cells and T cells transduced with a control CD33 VHH DARIC or CD33 VHH DARICs comprising a binding component that comprises a co-stimulatory domain were co-cultured with A549 cells engineered to express CD33, at an E:T ratio of 1 : 1, in the presence or absence of AP21967 for 24 hours. While untransduced and empty vector T cells produced minimal amounts of cytokines, T cells transduced with CD33 VHH DARIC produced IFNy ( Figure 1C) and IL-2 ( Figure ID) when cultured with CD33+ cells in the presence of rapalog.
- T cells transduced with CD33 VHH DARICs comprising a binding component that comprises a co- stimulatory domain also produced both IFNy and IL-2 when co-cultured with CD33+ tumor cells in the presence of rapalog.
- the amount of cytokines produced was comparable to the parental construct, with some co-stimulatory domains increasing cytokine production and some co-stimulatory domains decreasing cytokine production ( Figure 1C, ID).
- the impact of co-stimulatory domain on additional cytokine production was analyzed by Luminex.
- the untransduced T cells and T cells transduced with a control CD33 VHH DARIC or CD33 VHH DARICs comprising a binding component that comprises a co-stimulatory domain were co-cultured with A549 cells engineered to express CD33, at an E:T ratio of 1 : 1, in the presence of dimerizing drug for 24 hours.
- the supernatants were collected and analyzed for secretion of IFNy, IL-4, IL-6, IL-8, IL- 10, IL- 13, IL-17A, and MIP10 ( Figure IE).
- CD33 VHH DARIC Compared to CD33 VHH DARIC lacking a binding component with a co-stimulatory domain (grey bar), distinct cytokine production profiles were observed for CD33 VHH DARICs comprising a DARIC binding component comprising different co-stimulatory domains. Id.
- Control CD33 VHH DARIC lentiviral construct was designed, constructed, and verified as described in Example 1. Additional CD33 VHH DARIC lentiviral vectors were constructed comprising an MNDU3 promoter operably linked to a polynucleotide encoding: a DARIC signaling component (CD8a-signal peptide, an FRB variant (T82L), a transmembrane domain with or without a hinge region, an intracellular 4- IBB co- stimulatory domain, and a CD3 zeta signaling domain); a P2A sequence; and a DARIC binding component (an IgK-signal peptide, an anti-CD33 VHH, a G4S linker, a potential hinge, an FKBP12 domain, and a combination of different transmembrane domains with various hinge domains ( Figure 2A). See, e.g., SEQ ID NOs: 49-63. A CD33 VHH DARIC lacking hinge domains was used as a control.
- T cells from three donors were each transduced with LVVs encoding CD33 VHH DARIC containing DARIC signaling components and/or DARIC binding components various hinge domains or the parental CD33 VHH DARIC control and expanded for 10 days. All samples, including untransduced T cells and T cells transduced with empty vector, were stained with recombinant CD33-Fc reagent. While untransduced and empty vector T cells did not bind the staining reagent, T cells transduced with the control CD33 DARIC and CD33 DARIC s with different hinge domains were positively stained with the CD33-Fc staining.
- the untransduced T cells and T cells transduced with a control CD33 VHH DARIC or -CD33 VHH DARICs with different hinge domains were co-cultured with A549 cells engineered to express CD33, at an E:T ratio of 1 : 1, in the presence or absence of AP21967 for 24 hours. While untransduced and empty vector T cells produced minimal amounts of cytokine, T cells transduced with CD33 VHH DARICs without hinge domains produced IFNy ( Figure 2D) and IL-2 ( Figure 2E) when cultured with CD33+ cells in the presence of rapalog.
- T cells transduced with CD33 VHH DARICs containing a hinge domain also produced both IFNy and IL-2 when co-cultured with CD33+ tumor cells in the presence of rapalog.
- the amount of cytokines produced by CD33 VHH DARICs containing one or more hinge domains was comparable to the CD33 VHH DARIC control.
- Particular CD33 VHH DARICs containing one or more hinge domains increased or decreased cytokine production compared to controls ( Figure 2D&E).
- Tandem dual targeting anti-CD33/anti-CLLl VHH DARIC binding and signaling components were designed, constructed, and verified.
- the tandem dual-specificity VHH DARIC lentiviral vectors were constructed comprising an MNDU3 promoter operably linked to a polynucleotide encoding: a DARIC signaling component (CD8a-signal peptide, an FRB variant (T82L), a CD8a transmembrane domain with either an MH or LYC/LYS sequence, an intracellular 4-1BB costimulatory domain, and a CD3 zeta signaling domain); a P2A sequence; and a DARIC binding component (an IgK-signal peptide, a CD33 specific VHH binding domain, a 3xG4S linker, a CLL1 specific VHH binding domain (CLL-1.1 or CLL-1.2), a G4S linker, an FKBP12 domain, either a GGR or GGS linker/spacer,
- T cells from three donors were each transduced with LVVs encoding dualspecificity anti-CD33/anti-CLLl VHH DARICs ( Figure 3A) or controls and expanded for 10 days. All samples, including untransduced T cells, were stained with recombinant CLLl-Fc, CD33-Fc, or FRB-specific antibody reagents. While untransduced did not bind the staining reagent, tandem anti-CD33/anti-CLLl DARIC and controls were positively stained with all the detection reagents ( Figures 5A and 5B).
- T cells and T cells transduced with a tandem anti-CD33/anti-CLLl VHH DARIC were co-incubated with A549 cells engineered to express either CD33 or CLL1, at an E:T ratio of 1 : 1, normalized by FRB expression, in the presence or absence of rapamycin for 24 hours.
- T cells were also cultured in media alone or with a U- 937, a primary AML line that endogenously expresses both CD33 and CLL1. While untransduced T cells produced minimal amounts of cytokine, T cells transduced with tandem anti-CD33/anti-CLLl VHH DARIC produced IFNg when cultured with tumor cells in the presence of rapamycin.
- the amount of cytokine produced was mostly equivalent between all constructs, and all T cells produced minimal levels of IFNg in the absence of tumor cells ( Figures 6A and 6B).
- Tandem VHH DARIC binding and signaling components were designed, constructed, and verified. Tandem CAR molecules targeting multiple epitopes or antigens can be constructed by fusing two, or more, antigen targeting modalities in series. In the case of tandem molecules formed from at least two antigen binding domains the linker sequence connecting the antigen binding domains can be optimized for simplicity, flexibility, and for antigen binding and recognition ( Figures 3B and 7).
- tandem regulatable CAR molecules constructed from monovalent, single targeting, parental molecules specific from CD33 (SEQ ID NO: 64) and CLL1 (SEQ ID NOs: 65 and 66). The parental tandem molecules were initially constructed with a standard (Gly4Ser)3 linker (SEQ ID NOs:67 and 68).
- Optimized tandem VHH DARIC lentiviral vectors were constructed similar to the parental molecules comprising a MNDU3 promoter operably linked to a polynucleotide encoding: a DARIC signaling component (CD8a- signal peptide, an FRB variant (T82L), a CD8a transmembrane domain, an intracellular 4- 1BB costimulatory domain, and a CD3 zeta signaling domain); a P2A sequence; and a DARIC binding component (a human IgK-signal peptide, a CD33 specific VHH binding domain, a variable G4S or GGS linker, a CLL1 specific VHH binding domain, a G4S linker, an FKBP12 domain, and a CD4 transmembrane domain).
- the tandem constructs were constructed with the CD33 specific VHH in the membrane proximal position (SEQ ID NOs: 75-79). Untransduced T cells and parental tandem constructs were used as controls.
- DARIC T cells from three donors were each transduced with LVVs encoding CD33-CLL1 tandem constructs and expanded for 10 days.
- DARIC T cells were positively stained with CD33-Fc, CLLl-Fc and an anti-FRB monoclonal antibody by flow cytometry ( Figure 8A and 8B). All constructs labeled equivalently with the three labeling reagents detecting components of the DARIC constructs indicating that the linker composition does not materially affect expression or antigen recognition.
- Transduced T cells were co-cultured with CD33+ A549, CLL1+ A549, and the double positive AML cell line U937 ( Figures 9A and 9B) at an E:T ratio of 1 :1 in the presence or absence of InM rapamycin for 24 hours. All T cells transduced with DARIC construct exhibited robust cytokine response when co-cultured with the U937 AML cell line, in the presence of rapamycin. Minimal cytokine production was detected in T cell only, no target, samples. Cytokine was detected using MSD. Tandem constructs were also capable of eliminating single antigen positive A549 cell lines at approximately the same rate when co-cultured at an E:T ratio of 1 : 1. Tumor clearance was monitored by the loss of fluorescence associated with the tumor lines as measured by Incucyte.
- tandem regulatable CAR molecules constructed from monovalent, single targeting, parental molecules specific from CD33 (SEQ ID NO: 64) and CLL1 (SEQ ID NOs: 65 and 66) combining hinge, transmembrane, and linker sequences from Examples 3 and 4.
- Optimized tandem VHH DARIC lentiviral vectors were constructed similar to the parental molecules comprising a MNDU3 promoter operably linked to a polynucleotide encoding: a DARIC signaling component (CD8a-signal peptide, an FRB variant (T82L), a CD8a transmembrane domain with either an MH or LYC sequence, an intracellular 4-1BB costimulatory domain, and a CD3 zeta signaling domain); a P2A sequence; and a DARIC binding component (an IgK-signal peptide, a CD33 specific VHH binding domain, a G4S or 3xG4S linker (i.e., a (G4S)s), a CLL1 specific VHH binding domain, a G4S linker, an FKBP12 domain, either a GGR linker/spacer, and a CD4 transmembrane domain) ( Figure 3C and 10). See, e.g., S
- DARIC T cells from three donors were each transduced with LVVs encoding CD33-CLL1 tandem constructs and expanded for 10 days.
- DARIC T cells were positively stained with CD33-Fc, CLLl-Fc and an anti-FRB monoclonal antibody by flow cytometry ( Figures 11A and 1 IB). All constructs labeled equivalently with the three labeling reagents detecting components of the DARIC constructs indicating that the linker composition does not materially affect expression or antigen recognition.
- T cells and T cells transduced with a tandem anti-CD33/anti-CLLl VHH DARIC were co-incubated with A549 cells engineered to express either CD33 or CLL1, at an E:T ratio of 1 : 1, normalized by FRB expression, in the presence or absence of rapamycin for 24 hours.
- T cells were also cultured in media alone or with a HL60, an AML cell line that endogenously expresses both CD33 and CLL1. While untransduced T cells produced minimal amounts of cytokine, T cells transduced with tandem anti-CD33/anti-CLLl VHH DARIC produced IFNg when cultured with tumor cells in the presence of rapamycin. When normalized for FRB expression, the amount of cytokine produced was mostly equivalent between all constructs, and all T cells produced minimal levels of IFNg in the absence of tumor cells ( Figure 12A and 12B).
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Abstract
La présente divulgation concerne des compositions et des polypeptides ciblant CD33 améliorés, pour des thérapies adoptives à base de lymphocytes T pour le traitement, la prévention ou l'amélioration d'au moins un symptôme d'un cancer, d'une maladie infectieuse, d'une maladie auto-immune, d'une maladie inflammatoire, d'une immunodéficience ou d'un état pathologique associé.
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