WO2016014576A1 - Treatment of cancer using a cd33 chimeric antigen receptor - Google Patents

Treatment of cancer using a cd33 chimeric antigen receptor Download PDF

Info

Publication number
WO2016014576A1
WO2016014576A1 PCT/US2015/041390 US2015041390W WO2016014576A1 WO 2016014576 A1 WO2016014576 A1 WO 2016014576A1 US 2015041390 W US2015041390 W US 2015041390W WO 2016014576 A1 WO2016014576 A1 WO 2016014576A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
sequence
cell
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2015/041390
Other languages
English (en)
French (fr)
Inventor
Jennifer BROGDON
Hilmar Ebersbach
Saar GILL
David Glass
Thomas Huber
Julia JASCUR
Saad KENDERIAN
Joan Mannick
Michael C. MILONE
Leon Murphy
Celeste RICHARDSON
Reshma Singh
Huijuan SONG
Qilong WU
Jiquan Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
University of Pennsylvania Penn
Original Assignee
Novartis AG
University of Pennsylvania Penn
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to SG11201700416TA priority Critical patent/SG11201700416TA/en
Priority to AU2015292755A priority patent/AU2015292755B2/en
Priority to JP2017503497A priority patent/JP6831777B2/ja
Priority to MX2017001008A priority patent/MX390943B/es
Priority to EP15745069.3A priority patent/EP3172234B1/en
Priority to KR1020177004379A priority patent/KR102594343B1/ko
Priority to ES15745069T priority patent/ES2805475T3/es
Priority to BR112017001242A priority patent/BR112017001242A2/pt
Priority to RU2017105160A priority patent/RU2747384C2/ru
Priority to EP20160131.7A priority patent/EP3722316A1/en
Priority to CN201580050572.3A priority patent/CN107109419B/zh
Priority to CA2955154A priority patent/CA2955154C/en
Application filed by Novartis AG, University of Pennsylvania Penn filed Critical Novartis AG
Publication of WO2016014576A1 publication Critical patent/WO2016014576A1/en
Priority to ZA2017/00157A priority patent/ZA201700157B/en
Priority to IL250138A priority patent/IL250138B/en
Priority to CONC2017/0000510A priority patent/CO2017000510A2/es
Anticipated expiration legal-status Critical
Priority to AU2021200929A priority patent/AU2021200929A1/en
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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
    • C07K16/2851—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 lectin superfamily, e.g. CD23, CD72
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/421—Immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4202—Receptors, cell surface antigens or cell surface determinants
    • A61K40/4214—Receptors for cytokines
    • A61K40/4217—Receptors for interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • 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
    • C07K14/70517—CD8
    • 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
    • C07K14/7056—Lectin superfamily, e.g. CD23, CD72
    • 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
    • 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
    • C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3061—Blood cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction

Definitions

  • the present invention relates generally to the use of immune effector cells (e.g., T cells, NK cells) engineered to express a Chimeric Antigen Receptor (CAR) to treat a disease associated with expression of the Cluster of Differentiation 33 protein (CD33).
  • immune effector cells e.g., T cells, NK cells
  • CAR Chimeric Antigen Receptor
  • AML acute myeloid leukemia
  • RR-AML refractory AML
  • T cells can be transduced with genetic material encoding a single chain variable fragment (scFv) of an antibody, in conjunction with a signaling molecule, thereby using the complementarity determining region (CDR) to recognize a cell surface antigen in a non-MHC restricted manner.
  • CDR complementarity determining region
  • CAR chimeric antigen receptor
  • T cells whether it is a result of anergy, suppression or exhaustion can have effects on CAR-transformed T cells' performance. Skilled practitioners have limited control over the variability in the quality of T cells at this time.
  • CAR transformed patient T cells need to persist and maintain the ability to proliferate in response to the CAR's antigen. It has been shown that T cells from ALL patient can do this with CART19 comprising a murine scFv (see, e.g., Grupp et al., NEJM 368:1509-1518 (2013)).
  • the invention features an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antibody or antibody fragment which includes a CD33 binding domain (e.g., a human or humanized CD33 binding domain), a transmembrane domain, and an intracellular signaling domain (e.g., an intracellular signaling domain comprising a co stimulatory domain and/or a primary signaling domain).
  • CAR chimeric antigen receptor
  • the CAR comprises an antibody or antibody fragment which includes a CD33 binding domain described herein (e.g., a human or humanized CD33 binding domain described herein), a transmembrane domain described herein, and an intracellular signaling domain described herein (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain).
  • a CD33 binding domain described herein e.g., a human or humanized CD33 binding domain described herein
  • a transmembrane domain described herein e.g., a transmembrane domain described herein
  • an intracellular signaling domain described herein e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain.
  • the encoded CD33 binding domain comprises one or more (e.g., all three) light chain complementary determining region 1 (LC CDRl), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of a CD33 binding domain described herein, and/or one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDRl), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a CD33 binding domain described herein, e.g., a CD33 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs.
  • LC CDRl light chain complementary determining region 1
  • HC CDR2 light chain complementary determining region 2
  • HC CDR3 light chain complementary determining region 3
  • the encoded CD33 binding domain (e.g., a human or humanized CD33 binding domain) comprises a light chain variable region described herein (e.g., in Table 2 or 9) and/or a heavy chain variable region described herein (e.g., in Table 2 or 9).
  • the encoded CD33 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence of Table 2 or 9.
  • the encoded CD33 binding domain (e.g., an scFv) comprises a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 2 or 9, or a sequence with 95-99% identity with an amino acid sequence of Table 2 or 9; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 2 or 9, or a sequence with 95-99% identity to an amino acid sequence of Table 2 or 9.
  • modifications e.g., substitutions, e.g., conservative substitution
  • the encoded CD33 binding domain comprises a HC CDRl, a HC CDR2, and a HC CDR3 of any CD33 heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • the CD33 binding domain further comprises a LC CDRl, a LC CDR2, and a LC CDR3.
  • the CD33 binding domain comprises a LC CDRl, a LC CDR2, and a LC CDR3 of any CD33 light chain binding domain amino acid sequences listed in Table 2 or 9.
  • the encoded CD33 binding domain comprises one, two or all of
  • the encoded CD33 binding domain comprises an amino acid sequence sequence selected from a group consisting of SEQ ID NO:39-47, 57-65, 66-74, or 262-268.
  • the encoded CD33 binding domain (e.g., an scFv) comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO:39-47, 57-65, 66-74, or 262-268, or a sequence with 95-99% identity with an amino acid sequence of SEQ ID NO:39-47, 57-65, 66-74, or 262-268.
  • the encoded CD33 binding domain comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 57-65, or a sequence with 95-99% identity thereof.
  • the encoded CD33 binding domain comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 66-74, or a sequence with 95-99% identity thereof.
  • the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of SEQ ID NO: 255-261, or a sequence with 95-99% identity thereof.
  • the encoded CD33 binding domain includes a (Gly4-Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 3 or 4 (SEQ ID NO:26).
  • the light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region.
  • the encoded CAR includes a transmembrane domain that comprises a transmembrane domain of a protein, e.g., a protein described herein, e.g., selected from the group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD 137 and CD 154.
  • the encoded transmembrane domain comprises the sequence of SEQ ID NO: 6.
  • the encoded transmembrane domain comprises an amino acid sequence comprising at least one, two or three modifications, but not more than 20, 10 or 5 modifications of the amino acid sequence of SEQ ID NO:6, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:6.
  • the nucleic acid sequence encoding the transmembrane domain comprises the sequence of SEQ ID NO: 17, or a sequence with 95-99% identity thereof.
  • the encoded CD33 binding domain is connected to the
  • the encoded hinge region comprises SEQ ID NO:2, or a sequence with 95-99% identity thereof.
  • the nucleic acid sequence encoding the hinge region comprises the sequence of SEQ ID NO: 13, or a sequence with 95-99% identity thereof.
  • the isolated nucleic acid molecule further comprises a sequence encoding a costimulatory domain, e.g., a costimulatory domain described herein.
  • a costimulatory domain e.g., a costimulatory domain described herein.
  • the intracellular signaling domain comprises a costimulatory domain. In embodiments, the intracellular signaling domain comprises a primary signaling domain. In embodiments, the intracellular signaling domain comprises a costimulatory domain and a primary signaling domain.
  • the encoded costimulatory domain is a functional signaling domain obtained from a protein, e.g., described herein, e.g., selected from the group consisting of MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CDl la/CD18), 4-lBB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD 19, CD4, CD8alpha, CD8beta, IL2R
  • the encoded costimulatory domain comprises 4-lBB, CD27, CD28, or ICOS.
  • the encoded costimulatory domain of 4- IBB comprises the amino acid sequence of SEQ ID NO:7.
  • the encoded costimulatory domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:7, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:7.
  • the nucleic acid sequence encoding the costimulatory domain comprises the nucleotide sequence of SEQ ID NO: 18, or a sequence with 95-99% identity thereof.
  • the encoded costimulatory domain of CD28 comprises the amino acid sequence of SEQ ID NO:379.
  • the encoded costimulatory domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:379, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:379.
  • the nucleic acid sequence encoding the costimulatory domain of CD28 comprises the nucleotide sequence of SEQ ID NO:380, or a sequence with 95-99% identity thereof.
  • the encoded costimulatory domain of CD27 comprises the amino acid sequence of SEQ ID NO: 8.
  • the encoded costimulatory domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:8, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO: 8.
  • the nucleic acid sequence encoding the costimulatory domain of CD27 comprises the nucleotide sequence of SEQ ID NO: 19, or a sequence with 95-99% identity thereof.
  • the encoded costimulatory domain of ICOS comprises the amino acid sequence of SEQ ID NO:381.
  • the encoded costimulatory domain of ICOS comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:381, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:381,
  • the nucleic acid sequence encoding the costimulatory domain of ICOS comprises the nucleotide sequence of SEQ ID NO:382, or a sequence with 95-99% identity thereof.
  • the encoded primary signaling domain comprises a functional signaling domain of CD3 zeta.
  • the functional signaling domain of CD3 zeta comprises the amino acid sequence of SEQ ID NO: 9 (mutant CD3 zeta) or SEQ ID NO: 10 (wild type human CD3 zeta), or a sequence with 95-99% identity thereof.
  • the encoded intracellular signaling domain comprises a functional signaling domain of 4- IBB and/or a functional signaling domain of CD3 zeta.
  • the encoded intracellular signaling domain of 4- IBB comprises the amino acid sequence of SEQ ID NO: 7 and/or the CD3 zeta amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:7 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:7 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10.
  • the encoded intracellular signaling domain comprises the sequence of SEQ ID NO:7 and the sequence of SEQ ID NO:9 or SEQ ID NO: 10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the nucleic acid sequence encoding the intracellular signaling domain of 4-1BB comprises the nucleotide sequence of SEQ ID NO:18, or a sequence with 95-99% identity thereof, and/or the CD3 zeta nucleotide sequence of SEQ ID NO:20 or SEQ ID NO:21, or a sequence with 95-99% identity thereof.
  • the encoded intracellular signaling domain comprises a functional signaling domain of CD27 and/or a functional signaling domain of CD3 zeta.
  • the encoded intracellular signaling domain of CD27 comprises the amino acid sequence of SEQ ID NO: 8 and/or the CD3 zeta amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO: 8 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:8 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10.
  • the encoded intracellular signaling domain comprises the sequence of SEQ ID NO:8 and the sequence of SEQ ID NO:9 or SEQ ID NO: 10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the nucleic acid sequence encoding the intracellular signaling domain of CD27 comprises the nucleotide sequence of SEQ ID NO: 19, or a sequence with 95-99% identity thereof, and/or the CD3 zeta nucleotide sequence of SEQ ID NO:20 or SEQ ID NO:21, or a sequence with 95-99% identity thereof.
  • the encoded intracellular signaling domain comprises a functional signaling domain of CD28 and/or a functional signaling domain of CD3 zeta.
  • the encoded intracellular signaling domain of CD28 comprises the amino acid sequence of SEQ ID NO: 379 and/or the CD3 zeta amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:379 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:379 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the encoded intracellular signaling domain comprises the sequence of SEQ ID NO:379 and the sequence of SEQ ID NO:9 or SEQ ID NO: 10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the nucleic acid sequence encoding the intracellular signaling domain of CD28 comprises the nucleotide sequence of SEQ ID NO:380, or a sequence with 95-99% identity thereof, and/or the CD3 zeta nucleotide sequence of SEQ ID NO:20 or SEQ ID NO:21, or a sequence with 95-99% identity thereof.
  • the encoded intracellular signaling domain comprises a functional signaling domain of ICOS and/or a functional signaling domain of CD3 zeta.
  • the encoded intracellular signaling domain of ICOS comprises the amino acid sequence of SEQ ID NO: 381 and/or the CD3 zeta amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:381 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:381 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the encoded intracellular signaling domain comprises the sequence of SEQ ID NO:381 and the sequence of SEQ ID NO:9 or SEQ ID NO:10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the nucleic acid sequence encoding the intracellular signaling domain of ICOS comprises the nucleotide sequence of SEQ ID NO:382, or a sequence with 95-99% identity thereof, and/or the CD3 zeta nucleotide sequence of SEQ ID NO:20 or SEQ ID NO:21, or a sequence with 95-99% identity thereof.
  • the invention pertains to an isolated nucleic acid molecule encoding a CAR construct comprising a leader sequence, e.g., a leader sequence described herein, e.g., the amino acid sequence of SEQ ID NO: 1; a CD33 binding domain described herein, e.g., a CD33 binding domain comprising a LC CDR1, a LC CDR2, a LC CDR3, a HC CDR1, a HC CDR2 and a HC CDR3 described herein (e.g., a human or humanized CD33 binding domain described in Table 2 or 9), or a sequence with 95-99% identify thereof; a hinge region described herein, e.g., the amino acid sequence of SEQ ID NO:2; a transmembrane domain described herein, e.g., having a sequence of SEQ ID NO: 6; and an intracellular signaling domain, e.g., an intracellular signaling domain described herein.
  • a leader sequence e.g
  • the encoded intracellular signaling domain comprises a costimulatory domain, e.g., a costimulatory domain described herein (e.g., a 4- IBB costimulatory domain having the amino acid sequence of SEQ ID NO:7 or a CD27 costimulatory domain having the amino acid sequence of SEQ ID NO:8), and/or a primary signaling domain, e.g., a primary signaling domain described herein, (e.g., a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:9 or SEQ ID NO: 10).
  • the isolated nucleic acid molecule encoding the CAR construct includes a leader sequence encoded by the nucleic acid sequence of SEQ ID NO:l, or a sequence with 95-99% identity thereto.
  • the isolated nucleic acid molecule comprises (e.g., consists of) a nucleic acid encoding a CAR amino acid sequence of SEQ ID NO: 48, SEQ ID NO: 49,SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56; or an amino acid having one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g.,
  • the isolated nucleic acid molecule comprises (e.g., consists of) a nucleic acid sequence of SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO: 80, SEQ ID NO:81, SEQ ID NO: 82, or SEQ ID NO: 83 or a nucleic acid sequence having 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to a nucleic acid sequence of SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, or SEQ ID NO:83.
  • the invention pertains to an isolated nucleic acid molecule encoding a
  • CD33 binding domain wherein the CD33 binding domain comprises one or more (e.g., all three) light chain complementary determining region 1 (LC CDRl), light chain complementary determining region 2 (LC CDR2), and/or light chain complementary determining region 3 (LC CDR3) of a CD33 binding domain described herein, and one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDRl), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a CD33 binding domain described herein, e.g., a human or humanized CD33 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs.
  • the encoded CD33 binding domain comprises a HC CDRl, a
  • the CD33 binding domain further comprises a LC CDRl, a LC CDR2, and a LC CDR3.
  • the CD33 binding domain comprises a LC CDRl, a LC CDR2, and a LC CDR3 of any CD33 light chain binding domain amino acid sequences listed in Table 2 or 9.
  • the encoded CD33 binding domain comprises one, two or all of LC CDRl, LC CDR2, and LC CDR3 of any CD33 light chain binding domain amino acid sequences listed in Table 2 or 9, and one, two or all of HC CDRl, HC CDR2, and HC CDR3 of any CD33 heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • the encoded CD33 binding domain comprises a light chain variable region described herein (e.g., in SEQ ID NO:66, 67, 68, 69, 70, 71, 72, 73, or 74) and/or a heavy chain variable region described herein (e.g., in SEQ ID NO:57, 58, 59, 60, 61, 62, 63, 64, or 65).
  • the encoded CD33 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence of in SEQ ID NO:39, 40, 41, 42, 43, 44, 45, 46, or 47.
  • the CD33 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in SEQ ID NO: 66, 67, 68, 69, 70, 71, 72, 73, or 74, or a sequence with 95-99% identity with an amino acid sequence of SEQ ID NO: 66, 67, 68, 69, 70, 71, 72, 73, or 74; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of
  • the CD33 binding domain comprises a sequence selected from a group consisting of SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, and SEQ ID NO:47, or a sequence with 95-99% identify thereof.
  • the encoded CD33 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 2, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 2, via a linker, e.g., a linker described herein.
  • the encoded CD33 binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 26).
  • the light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region.
  • the invention pertains to an isolated CD33 binding domain (e.g., a polypeptide, antibody or fragment thereof) molecule encoded by the nucleic acid molecule.
  • the isolated CD33 binding domain comprises a sequence selected from the group consisting of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55 and SEQ ID NO:56, or a sequence with 95-99% identify thereof.
  • the invention pertains to an isolated chimeric antigen receptor
  • CD33 e.g., polypeptide
  • CD33 binding domain e.g., a human or humanized antibody or antibody fragment that specifically binds to CD33
  • transmembrane domain e.g., a transmembrane domain
  • intracellular signaling domain e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain
  • the CAR comprises an antibody or antibody fragment which includes a CD33 binding domain described herein (e.g., a human or humanized antibody or antibody fragment that specifically binds to CD33 as described herein), a transmembrane domain described herein, and an intracellular signaling domain described herein (e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain described herein).
  • a CD33 binding domain described herein e.g., a human or humanized antibody or antibody fragment that specifically binds to CD33 as described herein
  • a transmembrane domain described herein e.g., a transmembrane domain described herein
  • an intracellular signaling domain described herein e.g., an intracellular signaling domain comprising a costimulatory domain and/or a primary signaling domain described herein.
  • the CD33 binding domain comprises one or more (e.g., all three) light chain complementary determining region 1 (LC CDRl), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of a CD33 binding domain described herein, and one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDRl), heavy chain complementary determining region 2 (HC CDR2), and/or heavy chain complementary determining region 3 (HC CDR3) of a CD33 binding domain described herein, e.g., a CD33 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs.
  • LC CDRl light chain complementary determining region 1
  • HC CDR2 light chain complementary determining region 2
  • HC CDR3 light chain complementary determining region 3
  • the CD33 binding domain comprises a light chain variable region described herein (e.g., in Table 2) and/or a heavy chain variable region described herein (e.g., in Table 2 or 9).
  • the CD33 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence listed in Table 2 or 9.
  • the CD33 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 2 or 9, or a sequence with 95-99% identity with an amino acid sequence provided in Table 2 or 9; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g.,
  • the CD33 binding domain comprises a HC CDRl, a HC CDR2, and a HC CDR3 of any CD33 heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • the CD33 binding domain further comprises a LC CDRl, a LC CDR2, and a LC CDR3.
  • the CD33 binding domain comprises a LC CDRl, a LC CDR2, and a LC CDR3) ⁇ of any CD33 light chain binding domain amino acid sequences listed in Table 2 or 9.
  • the CD33 binding domain comprises one, two or all of LC CDRl, LC CDR2, and LC CDR3 of any CD33 light chain binding domain amino acid sequences listed in Table 2 or 9, and one, two or all of HC CDRl, HC CDR2, and HC CDR3 of any CD33 heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • the CD33 binding domain comprises a sequence selected from a group consisting of SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:57- 74, or SEQ ID NO:262-268; or am amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) to any of the aforesaid sequences; or a sequence with 95-99% identify to any of the aforesaid sequences.
  • substitutions e.g., conservative substitutions
  • the CD33 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 2 or 9, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 2 or 9, via a linker, e.g., a linker described herein.
  • the CD33 binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 26).
  • the light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region.
  • the isolated CAR molecule comprises a transmembrane domain of a protein, e.g., a protein described herein, e.g., selected from the group consisting of the the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 and CD154.
  • a protein e.g., a protein described herein, e.g., selected from the group consisting of the the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8,
  • the transmembrane domain comprises a sequence of SEQ ID NO: 6.
  • the transmembrane domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO: 6, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO: 6.
  • the CD33 binding domain is connected to the transmembrane domain by a hinge region, e.g., a hinge region described herein.
  • the encoded hinge region comprises SEQ ID NO:2, or a sequence with 95-99% identity thereof.
  • the isolated CAR molecule further comprises a sequence encoding a costimulatory domain, e.g., a costimulatory domain described herein.
  • the intracellular signaling domain of the isolated CAR molecule comprises a costimulatory domain. In embodiments, the intracellular signaling domain of the isolated CAR molecule comprises a primary signaling domain. In embodiments, the intracellular signaling domain of the isolated CAR molecule comprises a costimulatory domain and a primary signaling domain.
  • the costimulatory domain comprises a functional signaling domain of a protein selected from the group consisting of MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1
  • CDl la/CD18 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDl ld, ITGAE, CD103, ITGAL, CDl la, LFA-1, ITGAM, CDl lb, ITGAX, CDl lc, ITGB1, CD29, ⁇ 2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226),
  • the co stimulatory domain of 4- IBB comprises the amino acid sequence of SEQ ID NO:7.
  • the costimulatory domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO:7, or a sequence with 95- 99% identity to an amino acid sequence of SEQ ID NO:7.
  • the costimulatory domain of CD28 comprises the amino acid sequence of SEQ ID NO:379.
  • the costimulatory domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:379, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:379.
  • the costimulatory domain of CD27 comprises the amino acid sequence of SEQ ID NO: 8.
  • the costimulatory domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:8, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO: 8.
  • the costimulatory domain of ICOS comprises the amino acid sequence of SEQ ID NO:381.
  • the costimulatory domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:381, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:381.
  • the primary signaling domain comprises a functional signaling domain of CD3 zeta.
  • the functional signaling domain of CD3 zeta comprises SEQ ID NO: 9 (mutant CD3 zeta) or SEQ ID NO: 10 (wild type human CD3 zeta), or a sequence with 95-99% identity thereof.
  • the intracellular signaling domain comprises a functional signaling domain of 4- IBB and/or a functional signaling domain of CD3 zeta.
  • the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 7 and/or the amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 20, 10 or 5 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO: 7 and/or the sequence of SEQ ID NO:9 or SEQ ID NO: 10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO: 7 and/or the sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • modifications e.g., substitutions, e.g., conservative substitutions
  • substitutions e.g., conservative substitutions
  • the intracellular signaling domain comprises the amino acid sequence of SEQ ID NO: 7 and/or the sequence of SEQ ID NO:9 or SEQ ID NO: 10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the intracellular signaling domain comprises a functional signaling domain of CD27 and/or a functional signaling domain of CD3 zeta.
  • the intracellular signaling domain of CD27 comprises the amino acid sequence of SEQ ID NO: 8 and/or the CD3 zeta amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:8 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:8 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises the sequence of SEQ ID NO: 8 and the sequence of SEQ ID NO:9 or SEQ ID NO: 10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the intracellular signaling domain comprises a functional signaling domain of CD28 and/or a functional signaling domain of CD3 zeta.
  • the encoded intracellular signaling domain of CD28 comprises the amino acid sequence of SEQ ID NO: 379 and/or the CD3 zeta amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO: 379 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO: 379 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises the sequence of SEQ ID NO: 379 and the sequence of SEQ ID NO:9 or SEQ ID NO: 10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the intracellular signaling domain comprises a functional signaling domain of ICOS and/or a functional signaling domain of CD3 zeta.
  • the intracellular signaling domain of ICOS comprises the amino acid sequence of SEQ ID NO: 381 and/or the CD3 zeta amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the intracellular signaling domain comprises an amino acid sequence having at least one, two or three modifications but not more than 20, 10 or 5 modifications of an amino acid sequence of SEQ ID NO:381 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO:10, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:381 and/or an amino acid sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the encoded intracellular signaling domain comprises the sequence of SEQ ID NO:381 and the sequence of SEQ ID NO:9 or SEQ ID NO: 10, wherein the sequences comprising the intracellular signaling domain are expressed in the same frame and as a single polypeptide chain.
  • the isolated CAR molecule further comprises a leader sequence, e.g., a leader sequence described herein.
  • the leader sequence comprises an amino acid sequence of SEQ ID NO: 1, or a sequence with 95-99% identity to an amino acid sequence of SEQ ID NO:l.
  • the invention pertains to an isolated CAR molecule comprising a leader sequence, e.g., a leader sequence described herein, e.g., a leader sequence of SEQ ID NO: 1, or having 95-99% identity thereof, a CD33 binding domain described herein, e.g., a CD33 binding domain comprising a LC CDR1, a LC CDR2, a LC CDR3, a HC CDR1, a HC CDR2 and a HC CDR3 described herein, e.g., a CD33 binding domain described in Table 2, or a sequence with 95-99% identify thereof, a hinge region, e.g., a hinge region described herein, e.g., a hinge region of SEQ ID NO:2, or having 95-99% identity thereof, a transmembrane domain, e.g., a transmembrane domain described herein, e.g., a transmembrane domain having a sequence of SEQ ID NO: 6
  • the intracellular signaling domain comprises a costimulatory domain, e.g., a costimulatory domain described herein, e.g., a 4- IBB costimulatory domain having a sequence of SEQ ID NO:7, or having 95-99%identity thereof, and/or a primary signaling domain, e.g., a primary signaling domain described herein, e.g., a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:9 or SEQ ID NO: 10, or having 95-99% identity thereof.
  • a costimulatory domain e.g., a costimulatory domain described herein, e.g., a 4- IBB costimulatory domain having a sequence of SEQ ID NO:7, or having 95-99%identity thereof
  • a primary signaling domain e.g., a primary signaling domain described herein, e.g., a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:9 or S
  • the intracellular signaling domain comprises a costimulatory domain, e.g., a costimulatory domain described herein, e.g., a 4- IBB costimulatory domain having a sequence of SEQ ID NO:7, and/or a primary signaling domain, e.g., a primary signaling domain described herein, e.g., a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • a costimulatory domain e.g., a costimulatory domain described herein, e.g., a 4- IBB costimulatory domain having a sequence of SEQ ID NO:7
  • a primary signaling domain e.g., a primary signaling domain described herein, e.g., a CD3 zeta stimulatory domain having a sequence of SEQ ID NO:9 or SEQ ID NO: 10.
  • the isolated CAR molecule comprises (e.g., consists of) an amino acid sequence of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, or SEQ ID NO:56, or an amino acid sequence having at least one, two, three, four, five, 10, 15, 20 or 30 modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 60, 50 or 40 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, or SEQ ID NO:56, or an amino acid sequence having 85%, 90%, 95%, 96%, 97%, 98% or
  • the invention pertains to a CD33 binding domain comprising one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of a CD33 binding domain described herein, and/or one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain
  • HC CDR2 complementary determining region 2
  • HC CDR3 heavy chain complementary determining region 3
  • the CD33 binding domain comprises a HC CDRl, a HC CDR2, and a HC CDR3 of any CD33 heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • the CD33 binding domain further comprises a LC CDRl, a LC CDR2, and a LC CDR3.
  • the CD33 binding domain comprises a LC CDRl, a LC CDR2, and a LC CDR3) ⁇ of any CD33 light chain binding domain amino acid sequences listed in Table 2 or 9.
  • the CD33 binding domain comprises one, two or all of LC CDRl, LC CDR2, and LC CDR3 of any CD33 light chain binding domain amino acid sequences listed in Table 2 or 9, and one, two or all of HC CDRl, HC CDR2, and HC CDR3 of any CD33 heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • the CD33 binding domain comprises a light chain variable region described herein (e.g., in SEQ ID NO:66, 67, 68, 69, 70, 71, 72, 73, or 74) and/or a heavy chain variable region described herein (e.g. in SEQ ID NO:57, 58, 59, 60, 61, 62, 63, 64, or 65).
  • the CD33 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence of SEQ ID NO:39, 40, 41, 42, 43, 44, 45, 46, or 47.
  • the CD33 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications
  • substitutions e.g., conservative substitutions
  • the CD33 binding domain comprises a sequence selected from a group consisting of SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42, SEQ ID NO:43, SEQ ID NO:44, SEQ ID NO:45, SEQ ID NO:46, and SEQ ID NO:47, or a sequence with 95-99% identify thereof.
  • the CD33 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 2 or 9, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 2 or 9, via a linker, e.g., a linker described herein.
  • the CD33 binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 26).
  • the light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region.
  • the invention pertains to a vector comprising a nucleic acid molecule described herein, e.g., a nucleic acid molecule encoding a CAR described herein.
  • the vector is selected from the group consisting of a DNA, a RNA, a plasmid, a lentivirus vector, adenoviral vector, or a retrovirus vector.
  • the vector is a lentivirus vector.
  • the vector further comprises a promoter.
  • the promoter is an EF-1 promoter.
  • the EF-1 promoter comprises a sequence of SEQ ID NO: 11.
  • the promoter is a PGK promoter, e.g., a truncated PGK promoter as described herein.
  • the vector is an in vitro transcribed vector, e.g., a vector that transcribes RNA of a nucleic acid molecule described herein.
  • the nucleic acid sequence in the vector further comprises a poly(A) tail, e.g., a poly A tail described herein, e.g., comprising about 150 adenosine bases (SEQ ID NO: 377).
  • the nucleic acid sequence in the vector further comprises a 3'UTR, e.g., a 3' UTR described herein, e.g., comprising at least one repeat of a 3'UTR derived from human beta-globulin.
  • the nucleic acid sequence in the vector further comprises promoter, e.g., a T2A promoter.
  • the invention pertains to a cell comprising a vector described herein.
  • the cell is a cell described herein, e.g., an immune effector cell, e.g., a human T cell, e.g., a human T cell described herein, or a human NK cell, e.g., a human NK cell described herein.
  • the human T cell is a CD8+ T cell.
  • the CAR-expressing cell described herein can further express another agent, e.g., an agent which enhances the activity of a CAR-expressing cell.
  • the agent can be an agent which inhibits an inhibitory molecule.
  • inhibitory molecules include PDl, PD-L1, PD-L2, CTLA4, TIM3, CEACAM (e.g., CEACAM- 1, CEACAM-3 and/or CEACAM-5), LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GAL9, adenosine, and TGFR beta, e.g., as described herein.
  • the agent which inhibits an inhibitory molecule comprises a first polypeptide, e.g., an inhibitory
  • the agent comprises a first polypeptide, e.g., of an inhibitory molecule such as PDl, PD-L1, PD-L2, LAG3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), CTLA4, VISTA, CD160, BTLA, LAIR1, TIM3, 2B4,
  • an inhibitory molecule such as PDl, PD-L1, PD-L2, LAG3, CEACAM (e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), CTLA4, VISTA, CD160, BTLA, LAIR1, TIM3, 2B4,
  • a costimulatory domain e.g., 41BB, CD27 or CD28, e.g., as described herein
  • a primary signaling domain e.g., a CD3 zeta signaling domain described
  • the agent comprises a first polypeptide of PDl or a fragment thereof (e.g., at least a portion of the extracellular domain of PDl), and a second polypeptide of an intracellular signaling domain described herein (e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein).
  • a first polypeptide of PDl or a fragment thereof e.g., at least a portion of the extracellular domain of PDl
  • a second polypeptide of an intracellular signaling domain described herein e.g., a CD28 signaling domain described herein and/or a CD3 zeta signaling domain described herein.
  • the invention pertains to a method of making a cell comprising transducing a cell described herein, e.g., an immune effector cell described herein, e.g., a T cell described herein or an NK cell, with a vector of comprising a nucleic acid encoding a CAR, e.g., a CAR described herein.
  • the present invention also provides a method of generating a population of RNA- engineered cells, e.g., cells described herein, e.g., immune effector cells, e.g., T cells or NK cells, transiently expressing exogenous RNA.
  • the method comprises introducing an in vitro transcribed RNA or synthetic RNA into a cell, where the RNA comprises a nucleic acid encoding a CAR molecule described herein.
  • the invention pertains to a method of providing an anti-tumor immunity in a mammal comprising administering to the mammal an effective amount of a cell expressing a CAR molecule, e.g., a cell expressing a CAR molecule described herein.
  • the cell is an autologous immune effector cell, e.g., T cell or NK cell.
  • the cell is an allogeneic immune effector cell, e.g., T cell or NK cell.
  • the mammal is a human, e.g., a patient with a hematologic cancer.
  • the invention pertains to a method of treating a mammal having a disease associated with expression of CD33 (e.g., a proliferative disease, a precancerous condition, and a noncancer related indication associated with the expression of CD33) comprising administering to the mammal an effective amount of the cells expressing a CAR molecule, e.g., a CAR molecule described herein.
  • a disease associated with expression of CD33 e.g., a proliferative disease, a precancerous condition, and a noncancer related indication associated with the expression of CD33
  • a CAR molecule e.g., a CAR molecule described herein.
  • the mammal is a human, e.g., a patient with a hematologic cancer.
  • the disease is a disease described herein.
  • the disease associated with CD33 expression is selected from a proliferative disease such as a cancer or malignancy or a precancerous condition such as a myelodysplasia, a myelodysplasia syndrome or a preleukemia, or is a non-cancer related indication associated with expression of CD33.
  • the disease is a hematologic cancer selected from the group consisting of one or more acute leukemias including but not limited to acute myeloid leukemia (AML); myelodysplasia syndrome; myeloproliferative neoplasms; chronic myeloid leukemia (CML); Blastic plasmacytoid dendritic cell neoplasm; and to disease associated with CD33 expression including, but not limited to atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD33; and combinations thereof.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • CD33 Blastic plasmacytoid dendritic cell neoplasm
  • the cells expressing a CAR molecule are administered in combination with an agent that increases the efficacy of a cell expressing a CAR molecule, e.g., an agent described herein.
  • the invention pertains to a method of conditioning a subject prior to cell transplantation comprising administering to the subject an effective amount of the cell of comprising a CAR molecule disclosed herein.
  • the cell transplantation is a stem cell transplantation.
  • the stem cell transplantation is a hematopoietic stem cell
  • the cell transplantation is allogeneic or autologous.
  • the conditioning a subject prior to cell transplantation comprises reducing the number of CD33-expressing cells in a subject.
  • the CD33-expressing cells in the subject are CD33-expressing normal cells or CD33-expressing cancer cells, and in some cases, the condition in the subject will reduce both CD33-expressing normal and cancer cells prior to a cell transplantation.
  • the cells expressing a CAR molecule are administered in combination with a low, immune enhancing dose of an mTOR inhibitor.
  • a low, immune enhancing, dose e.g., a dose that is insufficient to completely suppress the immune system but sufficient to improve immune function
  • treatment with a low, immune enhancing, dose is accompanied by a decrease in PD-1 positive immune effector cells, e.g., T cells or NK cells, or an increase in PD-1 negative cells.
  • PD-1 positive immune effector cells e.g., T cells or NK cells
  • PD-1 negative immune effector cells e.g., T cells or NK cells
  • PD-1 ligand e.g., PD-L1 or PD-L2.
  • this approach can be used to optimize the performance of CAR cells described herein in the subject. While not wishing to be bound by theory, it is believed that, in an embodiment, the performance of endogenous, non-modified immune effector cells, e.g., T cells or NK cells, is improved. While not wishing to be bound by theory, it is believed that, in an embodiment, the performance of of a CD33 CAR expressing cell is improved.
  • cells e.g., immune effector cells (e.g., T cells or NK cells), which have, or will be engineered to express a CAR, can be treated ex vivo by contact with an amount of an mTOR inhibitor that increases the number of PDl negative immune effector cells, e.g., T cells NK cells, or increases the ratio of PDl negative immune effector cells, e.g., T cells or NK cells/ PDl positive immune effector cells, e.g., T cells or NK cells.
  • an mTOR inhibitor that increases the number of PDl negative immune effector cells, e.g., T cells NK cells, or increases the ratio of PDl negative immune effector cells, e.g., T cells or NK cells/ PDl positive immune effector cells, e.g., T cells or NK cells.
  • administering is initiated prior to administration of an CAR expressing cell described herein, e.g., immune effector cells (e.g., T cells or NK cells).
  • an mTOR inhibitor e.g., an allosteric inhibitor, e.g., RAD001, or a catalytic inhibitor
  • an CAR expressing cell described herein e.g., immune effector cells (e.g., T cells or NK cells).
  • the CAR cells are administered after a sufficient time, or sufficient dosing, of an mTOR inhibitor, such that the level of PDl negative immune effector cells, e.g., T cells or NK cells, or the ratio of PDl negative immune effector cells, e.g., T cells or NK cells/ PDl positive immune effector cells, e.g., T cells or NK cells, has been, at least transiently, increased.
  • an mTOR inhibitor such that the level of PDl negative immune effector cells, e.g., T cells or NK cells, or the ratio of PDl negative immune effector cells, e.g., T cells or NK cells/ PDl positive immune effector cells, e.g., T cells or NK cells, has been, at least transiently, increased.
  • the cell e.g., immune effector cell (e.g., T cell or NK cell), to be engineered to express a CAR
  • the cell is harvested after a sufficient time, or after sufficient dosing of the low, immune enhancing, dose of an mTOR inhibitor, such that the level of PDl negative immune effector cells, e.g., T cells, or the ratio of PDl negative immune effector cells, e.g., T cells or NK cells/ PDl positive immune effector cells, e.g., T cells or NK cells, in the subject or harvested from the subject has been, at least transiently, increased.
  • PDl negative immune effector cells e.g., T cells
  • the ratio of PDl negative immune effector cells e.g., T cells or NK cells/ PDl positive immune effector cells, e.g., T cells or NK cells
  • the invention provides an mTOR inhibitor for use in the treatment of a subject, wherein said mTOR inhibitor enhances an immune response of said subject, and wherein said subject has received, is receiving or is about to receive an immune effector cell that expresses a CD33 CAR as described herein.
  • the cells expressing a CAR molecule are administered in combination with an agent that ameliorates one or more side effect associated with administration of a cell expressing a CAR molecule, e.g., an agent described herein.
  • the cells expressing a CAR molecule are administered in combination with an agent that treats the disease associated with CD33, e.g., an agent described herein.
  • an agent that treats the disease associated with CD33 e.g., an agent described herein.
  • the disease associated with CD33 is a proliferative disease such as a cancer or malignancy or a
  • precancerous condition such as a myelodysplasia, a myelodysplasia syndrome or a
  • preleukemia or is a non-cancer related indication associated with expression of CD33.
  • the disease associated with CD33 is a hematologic cancer selected from the group consisting of one or more acute leukemias including but not limited to acute myeloid leukemia (AML); myelodysplasia syndrome; myeloproliferative neoplasms; chronic myeloid leukemia (CML); Blastic plasmacytoid dendritic cell neoplasm; and to disease associated with CD33 expression including, but not limited to atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD33; and combinations thereof.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • CD33 Blastic plasmacytoid dendritic cell neoplasm
  • CD33 expression including, but not limited to atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases expressing CD33; and combinations thereof.
  • a CD33 CAR described herein targets a CD33-expressing cell. In embodiments, the CD33 CAR described herein targets an MDS blast. In some
  • the MDS blast comprises a 5q deletion (del(5q)).
  • a CD33 CAR-expressing cell described herein is used to treat a subject having MDS.
  • a CD33 CAR-expressing cell described herein is used to treat a subject having MDS associated with isolated del(5q).
  • a CD33 CAR described herein targets a MDSC, e.g., a MDSC in a subject having a cancer (e.g., multiple myeloma, chronic lymphocytic leukemia, or solid malignancies such as ovarian cancer, colon cancer, or breast cancer).
  • a cancer e.g., multiple myeloma, chronic lymphocytic leukemia, or solid malignancies such as ovarian cancer, colon cancer, or breast cancer.
  • the MDSC is lineage negative (LIN-), HLA-DR negative, and CD33 positive.
  • a CD33 CAR-expressing cell described herein targets a MDS blast and a MDSC.
  • a CD33 CAR-expressing cell described herein is used to treat multiple myeloma, chronic lymphocytic leukemia (CLL), or solid malignancies such as ovarian cancer, colon cancer, or breast cancer.
  • CLL chronic lymphocytic leukemia
  • the invention pertains to the isolated nucleic acid molecule encoding a CAR of the invention, the isolated polypeptide molecule of a CAR of the invention, the vector comprising a CAR of the invention, and the cell comprising a CAR of the invention for use as a medicament, e.g., as described herein.
  • the invention pertains to a the isolated nucleic acid molecule encoding a CAR of the invention, the isolated polypeptide molecule of a CAR of the invention, the vector comprising a CAR of the invention, and the cell comprising a CAR of the invention for use in the treatment of a disease expressing CD33, e.g., a disease expressing CD33 as described herein.
  • a disease expressing CD33 e.g., a disease expressing CD33 as described herein.
  • the CD33 CAR molecule e.g., a CD33 CAR nucleic acid or a CD33 CAR polypeptide as described herein), or the CD33 binding domain as described herein, includes one, two or three CDRs from the heavy chain variable region (e.g., HC CDRl, HC CDR2 and/or HC CDR3), provided in Table 3; and/or one, two or three CDRs from the light chain variable region (e.g., LC CDRl, LC CDR2 and/or LC CDR3) of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 4; or a sequence substantially identical (e.g., 95-99% identical, or up to 5, 4, 3, 2, or 1 amino acid changes, e.g., substitution
  • the CD33 CAR molecule e.g., a CD33 CAR nucleic acid or a
  • CD33 CAR polypeptide as described herein), or the anti-CD33 antigen binding domain as described herein includes one, two or three CDRs from the heavy chain variable region (e.g., HC CDRl, HC CDR2 and/or HC CDR3), provided in Table 10; and/or one, two or three CDRs from the light chain variable region (e.g., LC CDRl, LC CDR2 and/or LC CDR3) of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 11; or a sequence substantially identical (e.g., 95-99% identical, or up to 5, 4, 3, 2, or 1 amino acid changes, e.g., substitutions (e.g., conservative substitutions)) to any of the aforesaid sequences.
  • the heavy chain variable region e.g., HC CDRl, HC CDR2 and/or
  • the CD33 CAR molecule, or the anti-CD33 antigen binding domain includes one, two or three CDRs from the heavy chain variable region (e.g., HCDR1, HCDR2 and/or HCDR3), provided in Table 12; and/or one, two or three CDRs from the light chain variable region (e.g., LC CDRl, LC CDR2 and/or LC CDR3) of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 13; or a sequence substantially identical (e.g., 95-99% identical, or up to 5, 4, 3, 2, or 1 amino acid changes, e.g., substitutions (e.g., conservative substitutions)) to any of the aforesaid sequences.
  • the heavy chain variable region e.g., HCDR1, HCDR2 and/or HCDR3
  • the light chain variable region e.g
  • the CD33 CAR molecule, or the anti-CD33 antigen binding domain includes
  • the CD33 CAR molecule e.g., a CD33 CAR nucleic acid or a CD33 CAR polypeptide as described herein, or the anti-CD33 antigen binding domain as described herein, includes:
  • LC CDRs chosen from one of the following:
  • HC CDRs chosen from one of the following:
  • the CD33 CAR molecule e.g., a CD33 CAR nucleic acid or a CD33 CAR polypeptide as described herein, or the anti-CD33 antigen binding domain as described herein, includes:
  • LC CDRs chosen from one of the following:
  • HC CDRs chosen from one of the following:
  • the CD33 CAR molecule e.g., a CD33 CAR nucleic acid or a
  • CD33 CAR polypeptide as described herein), or the anti-CD33 antigen binding domain as described herein, includes:
  • LC CDRs chosen from one of the following:
  • HC CDRs chosen from one of the following:
  • the CD33 CAR molecule e.g., a CD33 CAR nucleic acid or a CD33 CAR polypeptide as described herein
  • the anti-CD33 antigen binding domain as described herein includes the 2213 scFv amino acid sequence (SEQ ID NO:
  • nucleotide sequence encoding the 2213 scFv (SEQ ID NO: 141), or an antigen binding domain thereof (e.g., a VH, VL or one or more CDRs thereof).
  • the CD33 CAR molecule e.g., a CD33 CAR nucleic acid or a CD33 CAR polypeptide as described herein
  • the anti-CD33 antigen binding domain as described herein includes the my96 scFv amino acid sequence (SEQ ID NO:
  • an antigen binding domain thereof e.g., a VH, VL or one or more CDRs
  • Figures 2A, 2B, and 2C are graphs and a flow cytometry profile showing the expression of CD33 in bone marrow from myelodysplasia syndrome patients.
  • Figure 2A shows the percentage of CD33-expressing cells in the CD34+ CD38- hematopoietic stem cell compartment in MDS patients.
  • Figure 2B shows the percentage of CD33-expressing cells in the CD34+ CD38+ compartment containing myeloid progenitors in MDS patients.
  • Figure 2C is a histogram showing the mean fluorescence intensity from an MDS patient in the CD34+ CD38- compartment.
  • FIG. 3 shows a schematic representation of CAR constructs used in Example 1. All are second generation CARs using 41BB and CD3zeta signaling.
  • the scFv of CART33 was derived from clone MY9-6.
  • FIG 4 is an image demonstrating in vitro activity of CART33.
  • CART33- mediated T cell degranulation CAR33-transduced and untransduced T cells were incubated with the CD33+ cell line MOLM14 and a control ALL cell line NALM6 for 4 hours in the presence of CD28, CD49d and monensin. CD107a degranulation was measured by flow cytometry. Expression of both murine and humanized CART33 constructs elicit specific degranulation in the presence of MOLM14 (P ⁇ 0.001).
  • FIG. 5 is an image demonstrating in vitro activity of CART33.
  • Cytokine production both humanized and murine CAR33 expressing T cells produce cytokine after incubation with MOLM14. T cells were incubated with the CD33+ cell line MOLM14 and a control cell line NALM6 for 4 hours. Cells were then fixed, permeabilized and stained for intracellular tumor necrosis alpha and interferon gamma. Samples were then alayzed by by flow cytometry.
  • FIG. 6 is an image demonstrating in vitro activity of CART33.
  • Proliferation of CAR123- and CAR33-expressing T cells humanized CART33 and murine CART33 proliferation in response to MOLM14.
  • T cells were labeled with CFSE and incubated under control conditions or with MOLM14 for 120 hours and CFSE dilution was measured by flow cytometry as a marker of proliferation.
  • Figures 7 A and 7B are two graphs demonstrating in vitro activity of CART33. Specific killing of CAR123-, humanized CAR33-, and murine CAR33-expressing T cells: T cells were incubated with MOLM14 or the T-cell ALL cell line Jurkat (control) for 24 hours.
  • huCART33 resulted in significantly more specific killing compared to murine CART33 at low E:T ratios.
  • CART33-Jurkat is represented by triangles
  • CART33-MOLM14 is represented by upside down triangles
  • CART123-MOLM14 is represented by squares.
  • Figure 8 is an image demonstrating CART33 (IgG4 hinge) and CART33 (CD 8 hinge) have equivalent in vitro activity.
  • Degranulation assay CART33 (IgG4 hinge), CART33 (CD8 hinge), CART123, and untransduced T cells were incubated with the CD33+ cell line MOLM14 and CD107a degranulation was measured by flow cytometry. Both CART33 constructs undergo specific degranulation in the presence of MOLM14.
  • Figure 9 is an image demonstrating CART33 (IgG4 hinge) and CART33 (CD 8 hinge) have equivalent in vitro activity.
  • Cytokine production both CAR33 constructs and CAR123 specifically induce cytokine production after incubation with the MOLM14 cell line. T cells were incubated with MOLM14 for 4 hours in the presence of CD28, CD49d and monensin. Cells were then harvested, fixed, permalized and stained for tumor necrosis alpha, MlPla and interferon gamma. Percentage of cells producing cytokines were then measured by flow cytometry.
  • Figure 10 is an image demonstrating CART33 (IgG4 hinge) and CART33 (CD8 hinge) have equivalent in-vitro activity. Proliferation of control untransduced, CAR33- (IgG4 hinge) (i.e., CAR33-IgG4H), CAR33- (CD 8 hinge) (i.e., CAR33-CD8H), or CAR123- expressing T cells in response to MOLM14. T cells were labeled with CFSE and incubated with MOLM14 for 120 hours.
  • FIG 11 is a schematic diagram demonstrating a comparison of in vivo anti-tumor effect of CART33-CD8H, CART33-IgG4H, and CART 123.
  • NOD-SCID- common gamma chain knockout (NSG) mice were injected with the AML cell line MOLM14 lxlO 6 i.v. and imaged for engraftment after 6 days. On day 7, mice were treated with T cells expressing CAR33 (IgG4 hinge), CAR33 (CD 8 hinge), CAR123, or control vehicle (untransduced cells). Total number of T cells injected was 2 x 10 6 i.v. The mice were followed with serial weekly imaging to assess tumor burden.
  • BLI bioluminescent imaging
  • FIG. 13 is a schematic diagram demonstrating a comparison of CART33 and CART123 eradication of primary AML in vivo.
  • NSG mice transgenic for the human cytokines IL3/GM-CSF/SCF (NSGS mice) were injected with a primary AML sample at 5xl0 6 i.v. Engraftment was confirmed by retro-orbital bleeding after 2-4 weeks and then mice were treated with CART33, CART123, or control vehicle (untransduced cells). Total number of T cells injected was lxlO 5 i.v. The mice were followed with serial retro-orbital bleedings to assess the burden of AML.
  • Figure 14 is an image demonstrating CART33 and CART123 produce equivalent eradication of primary AML in vivo. Analysis of peripheral blood from mice treated with untransduced (UTD), CART33 or CART 123 at baseline, day 14 and day +70. AML according to the experimental set-up described in Figure 13 was not detected in mice treated with CART33 or CART 123.
  • Figure 15 is an image demonstrating CART33 and CART123 produce equivalent eradication of primary AML in vivo. Summary of disease burden measured by blasts/ul from retro-orbital bleedings at different time points as indicated from mice in experimental set-up described in Figure 13.
  • Figure 16 is an image demonstrating CART33 and CART123 produce equivalent eradication of primary AML in vivo. Survival of mice treated with CART33, CART123 or
  • FIG 17 is a schematic diagram demonstrating a set-up for testing hematopoietic stem cell toxicity of CART33 cells.
  • HIS humanized immune system
  • mice were then euthanized on day 28 and organs were harvested and analyzed.
  • Figure 18 is an image demonstrating hematopoietic stem cell toxicity of CART33 cells. Analysis of the peripheral blood (via retro-orbital bleeding) by flow cytometry from day
  • CART33 treatement leads to significant reduction in peripheral blood myeloid cells and monocytes compared to treatment with untransduced T cells.
  • Figure 20 is an image demonstrating hematopoietic stem cell toxicity of CART33 cells. Plots from bone marrow analysis by flow cytometry on day 28 of mice from the experiment shown in Figure 17. CART33 treatment resulted in significant reduction in myeloid progenitors (CD34+CD38+) and in hematopoietic stem cells (CD34+CD38-), gated on singlets, huCD45dim, Lineage negative.
  • CD34+CD38+ myeloid progenitors
  • CD34+CD38- hematopoietic stem cells
  • Figure 21 is an image demonstrating hematopoietic stem cell toxicity of CART33 cells. Sections of the femur of mice from the experiment shown in Figure 17 were taken from the mice on day 28 after treatment with UTD T cells or CART33 cells. huCD45 and CD34 staining by IHC was performed. No difference in huCD45 between control T cells and
  • Figure 22 is a schematic diagram demonstrating a set-up for testing CART33 and CART123 hematopoietic toxicity in vivo.
  • Schema of the experiment NSGS mice received busulfan i.p. followed by 2xl0 6 T cell depleted bone marrow cells from a normal donor the following day. Engraftment was confirmed by flow cytometric analysis of peripheral blood after 4 weeks and mice were then treated with lxlO 6 autologous T cells, transduced with
  • Figure 23 is an image demonstrating CART33 and CART123 produce equivalent hematopoietic toxicity in vivo. Shown is a representative plot of bone marrow analysis from mice from the experiment shown in Figure 22 by flow cytometry on day 28. CART33 and CART123 treatment resulted in significant reduction in myeloid progenitors (CD34+CD38+) and in hematopoietic stem cells (CD34+CD38-), gated on huCD45dim, Lin-. Results are representative of two experiments.
  • Figure 24 is an image demonstrating CART33 and CART123 are cytotoxic myelodysplasia syndrome (MDS) marrow cells.
  • CD34 enriched BM from patients with MDS was incubated with either UTD, CART33 (IgG4 hinge), CART33 (CD 8 hinge), or CART 123. There was reduction in CD45dimCD34+ cells in samples treated with CART33 or CART123.
  • Figure 25 is a schematic diagram of a vector for expressing a murine CART33.
  • Figure 26 is a schematic diagram of a vector for expressing a humanized CART33.
  • Figure 27 is an image depicting the cell surface expression of scFvs on a Jurkat T cell line, which contains a luciferase reporter driven by an NFAT-regulated promoter (termed JNL cells).
  • JNL cells were transduced with a lentiviral vector expressing a cDNA encoding GFP, a scFv that binds to CD 19, or cDNAs that encode an scFv, which was raised against hsCD33.
  • the cell surface expression of individual scFv's on JNLs was detected by incubating cells with recombinant Fc-tagged hsCD33 followed by incubation with an Fc-specific secondary antibody conjugated to phycoerythrin.
  • Figures 28A, 28B, 28C, and 28D are images showing the ability of individual scFv's targeting hsCD33 to elicit NFAT activity in JNL cells.
  • JNL cells expressing scFv's against hsCD33 were co-cultured with MOLM13 or MOLP8 cell lines, which express hsCD33 or lack hsCD33 cell surface expression, respectively (Figure 28A; hsCD33, solid green line; isotype control, gray dashed line and shaded area).
  • Figure 28B depicts the activation of JNL cells expressing an scFv targeting hsCD33 in the presence of MOLM13 (solid lines) or MOLP8 (dashed lines) cells.
  • FIG. 28C is a version of Figure 28B, depicting the activation of JNL cells in the presence of MOLM13.
  • Figure 28D is a version of Figure 28B, depicting the activation of JNL cells in the presence of MOLP8.
  • Figures 29A and 29B are panels of images depicting the activity of scFv's targeting hsCD33 in donor-derived primary T cells. Expression of scFv's on the cell surface of primary human T cells transduced with a lentiviral vector that expresses an scFv that targets hsCD33 is depicted. The expression of scFv's was detected by incubating cells with recombinant Fc- tagged hsCD33 and an Fc-specific secondary antibody conjugated to phycoerythrin as described in Figure 27.
  • Figures 30A and 30B are images depicting the proliferative activity of T cells expressing scFvs targeting CD33.
  • T cells were labeled with CFSE and co-cultured in the presence of MOLM13 (Figure 30A, solid black bar), MOLP8 ( Figure 30A, open white bar), or cultured alone ( Figure 30A, hatched bar) to assess the proliferative capacity of UTD primary T cells or cells expressing scFvs targeting hsCD33.
  • Figure 31 is an image depicting cytolytic activity of T cells expressing scFVs targeting CD33.
  • 25,000 MOLM13 cells were plated with primary T cells expressing individual scFv's at different effector (i.e T cell) to target (i.e. MOLM13) ratios and analyzed for the extent of MOLM13 killing by enumerating the absolute number of CFSE-labeled MOLM 13 cells after 4 days in culture.
  • Figure 32 is an image depicting cross-reactivity of T cells expressing scFvs targeting CD33 to cynomolgus CD33 (cyCD33) by flow cytometry.
  • JNL cells transduced with a lentiviral vector expressing scFv's raised against hsCD33 were incubated with either recombinant Fc-tagged hsCD33 (dotted line) or cyCD33 (solid line) followed by incubation with an Fc-specific secondary antibody conjugated to phycoerythrin.
  • Figures 33A and 33B depict the expression of an mRNA CAR33 in T cells from normal donors after electroporation.
  • Figure 33A is a series of flow cytometry profiles showing the expression of CAR33 in the T cell population at the indicated time points. The percentage of CAR33-expressing cells (boxed) are quantified and shown in the profile.
  • Figure 33B is a graphic representation of the percentage of CAR33 expression.
  • Figures 34A and 34B compare the expression of lentivirally-transduced CAR33 to mRNA-electroporated CAR33.
  • Figure 34A shows the stable expression of lentivirally- transduced CAR33 (CART33LV) at the indicated times, over 4 days.
  • Figure 34B shows the transient expression of mRNA-electroporated CAR33 (CART33 RNA) at the indicated times, over 4 days.
  • the expression of CAR33 is represented by mean fluorescence intensity (MFI) on the x-axis, and total cell number is represented on the y-axis.
  • Figures 35A, 35B, 35C, and 35D are graphic representations comparing the cytolytic activity of T cells expressing CD33 after lentiviral transduction or mRNA
  • Figures 36A and 36B are graphic representations comparing the cytolytic activity of T cells expressing CD33 after lentiviral transduction or mRNA electroporation over time.
  • Figure 36A shows the specific killing of lentivirally-transduced CAR33 cells compared to RNA CAR33 cells when incubated with MOLM14 cells at the E:T (effectontarget) ratio of 2:1 over 4 days.
  • Figure 36B shows the specific killing of lentivirally-transduced CAR33 cells compared to RNA CAR33 cells when incubated with MOLM14 cells at the E:T (effector: target) ratio of 1:1 over 4 days.
  • Figures 37A, 37B, 37C, and 37D show that CART33 cells exhibit robust in vitro effector functions in response to the CD33+ cell line MOLM14 or to primary AML samples. Plots are representative of four independent experiments.
  • Figure 37 A shows the CD 107a degranulation. CART33, CART123 and untransduced T cells (UTD) were incubated with the CD33+/CD123+ cell line MOLM14, PMA/Ionomycin as positive non specific T cell stimulant and the control T cell ALL cell line Jurkat, in the presence of CD49d, CD28 costimulatory molecules and momensin. CD 107a degranulation was measured by flow cytometry after 4 hours of incubation.
  • Figure 37B shows the specific killing of CD33-expressing cells.
  • CART33, CART123 and UTD were incubated with MOLM14-luc or Jurkat-luc for 24 hours at different E:T ratios as indicated and bioluminescence imaging was then performed as a measure of residual living cells.
  • the black/solid line (squares) represents CART123 incubated with
  • FIG. 37C and 37D show the proliferation of CART33 cells in response to CD33-expressing cells.
  • T cells were labeled with CFSE and incubated with MOLM14, PMA/IONO as positive non specific T cell stimulant, Jurkat as a negative control, or AML samples for 120 hours. The number of proliferating T cells was significantly higher in response to MOLM14 as compared to Jurkat and was comparable to CART 123.
  • Figures 38A, 38B, and 38C show the cytokine production by CART33 cells in response to CD33-expressing cells MOLM14.
  • CART33, CART 123 and UTD cells were incubated with MOLM14, PMA/Ionomycin, and Jukat for 4 hours. The cells were then fixed and permeabilized, stained for 5 different cytokines (Tumor necrosis factor alpha, interferon gamma, granulocyte macrophage colony stimulating factor, macrophase inflammatory protein lb, and interleukin-2), and flow cytometric analyses were performed.
  • the majority of CAR T33 cells produce more than one cytokine in response to MOLM14 (Figure 38A), similar to their response to PMA/Ionomycin (positive control, Figure 38B).
  • Figure 38C shows the production of IL-2, IFN- ⁇ , GM-CSF, and TNF-cc in response to MOLM14 was significantly higher in CART33 than CART 123 cells.
  • CART33, CART 123 and UTD cells were incubated with MOLM14, Jurkat and PMA/Ionomycin for 24 hours. Supernatant was then harvested and a 30-plex Luminex assay was performed. Levels of the rest of cytokines are presented in Figure 39.
  • Figure 39 is a series of graphs showing the comparison of cytokine production by CART33 and CART 123 cells in response to MOLM14.
  • CART33, CART 123 and UTD cells were incubated with MOLM14, Jurkat and PMA/Ionomycin for 24 hours. Supernatant was then harvested and a 30-plex Luminex assay was performed for the indicated cytokines.
  • Figure 40 shows the specific killing of CD33-expressing MOLM14 cells in vitro.
  • CART 123, CART33 (CD 8 hinge) and CART33 (IgG4 hinge) were incubated with MOLM14 at the indicated E:T ratios and killing was assessed by bioluminescence imagine.
  • CART33 (IgG4 hinge) resulted in more specific killing than CART33 (CD8 hinge) at lower E:T ratio.
  • Figures 41 A, 41B, and 41C show the anti-tumor activity in myelodysplasia syndromes (MDS).
  • Figure 41A is a graph showing specific CD107a degranulation in response to bone marrow cells from MDS patients.
  • Figure 41B is a set of images showing specific killing of the MDS clone having 5q deletion.
  • Figure 41C is a graph showing the quantification of 5q deletion clones remaining after treatment as determined by FISH. There was significant reduction in the 5q- clone percentage in the group treated with CART33 when compared to UTD and No treatment groups.
  • Figures 42A, 42B, 42C show the CART33 treatment and survival results from MOLM14 engrafted xenografts.
  • the experimental schema is presented in Figure 11.
  • Figure 42B shows the composite survival of three independent experiments. Treatment with CART33 resulted in significant survival advantages when compared with treatment with UTD.
  • Figure 42C are representative bioluminescence images from one experiment.
  • Figures 43A and 43B show CART33 treatment result in a dose dependent reduction of leukemia burdenin MOLM14 engrafted xenografts.
  • Figure 43 A is a schematic showing an experimental set-up described in Example 6.
  • Figure 43B shows the quantification of the tumor burden over time as measured by bioluminescent imaging (BLI) in different groups.
  • Figure 44 is a graph showing the tumor burden over time as measured by bioluminescent imaging (BLI) in the different groups in the experimental set-up shown in Figure 11.
  • BLI bioluminescent imaging
  • Figure 45 shows the combination of RNA-CART33 and chemotherapy result in further reduction of leukemic burden in MOLM14 engrafted xenografts.
  • Figures 46A and 46B show the antibody binding capacity of CD33 and CD123 on
  • MOLM14 and Primary AML samples used for in vivo experiments were performed using QUANTUM SIMPLY CELLULAR kit (Bangs Laboratories, Inc). Samples were washed in flow buffer and then stain with the indicated antibody (CD33 or CD123) conjugated to PE. The five different microspheres provided in the kit were also stained with the same antibody. The mean fluorescence intensity of the target was compared to that of the five microspheres and the value of antibody binding capacity was then calculated per the manufacture protocol.
  • Figure 46A shows the antibody binding capacity of MOLM14 for CD33 and CD123
  • Figure 46B showst the antibody binding capacity of the primary samples used in these experiments for CD33 and CD123.
  • Figure 47 is a graph showing the proliferation by cell count of various T cells—
  • CART-33 T cells CD33-1 through CD33-9, or Upenn
  • CART-CD 19 T cells CD19
  • unstransduced T cells Cell
  • Figure 48A is a graph showing the percent of HL-60-Luc target cell lysis when exposed to various CART-33 T cells (CD33-1 through CD33-9, or Upenn), CART-CD 19 T cells (CD 19), or unstransduced T cells (Cell) at various effector to T cell ratios.
  • Figure 48B is a graph showing the percent of PL21/Luc target cell lysis when exposed to various CART-33 T cells (CD33-1 through CD33-9, or Upenn), CART-CD 19 T cells (CD19), or unstransduced T cells (Cell) at various effector to T cell ratios.
  • Figure 48C is a graph showing the percent of U87/Luc target cell lysis when exposed to various CART-33 T cells (CD33-1 through CD33-9, or Upenn), CART-CD 19 T cells (CD 19), or unstransduced T cells (Cell) at various effector to T cell ratios.
  • Figure 49 is a graph showing the concentration of cytokines (human interferon- gamma (IFN- ⁇ ), human interleukin-2 (IL-2), and human tumor necrosis factor (TNF)) produced by various CART-33 T cells (CD33-1 through CD33-9, or Upenn), CART-CD 19 T cells (CD19), or unstransduced T cells (Cell) when exposed to PL21, HL60, or MOLP8 target cells.
  • cytokines human interferon- gamma (IFN- ⁇ ), human interleukin-2 (IL-2), and human tumor necrosis factor (TNF)
  • Figure 50A is a flow cytometry plot showing the gating strategy for MDSCs.
  • Figure 50B is a graph showing the percent of lineage negative, HLA-DR negative, CD33+ (LIN-
  • FIG. 50C is a graph showing the level of CD33 measured by mean fluorescence intensity (MFI) in the MDSC population (MDSCs) compared to malignant MDS population (MDS) and normal donor population (ND-BM).
  • MFI mean fluorescence intensity
  • Figure 51A is a panel of flow cytometry plots showing the extent of degranulation
  • CD 107a level and cytokine production (GM-CSF, IL-2, TNF-a) from CART33.
  • CD 107a degranulation and cytokine production are shown on the y-axis, and anti-CD33 CAR on the x- axis.
  • the negative control is shown on the left (Jurkat) and the MDSC on the right.
  • Figure 5 IB is a graph showing the quantification of degranulation and cytokine production by
  • Figure 52A-52D show the various configurations on a single vector, e.g., where the U6 regulated shRNA is upstream or downstream of the EFl alpha regulated CAR encoding elements.
  • the transcription occurs through the U6 and EFl alpha promoters in the same direction.
  • the transcription occurs through the U6 and EFl alpha promoters in different directions.
  • the shRNA (and corresponding U6 promoter) is on a first vector
  • the CAR (and corresponding EFl alpha promoter) is on a second vector.
  • Figure 53 depicts the structures of two exemplary RCAR configurations.
  • the antigen binding members comprise an antigen binding domain, a transmembrane domain, and a switch domain.
  • the intracellular binding members comprise a switch domain, a co- stimulatory signaling domain and a primary signaling domain.
  • the two configurations demonstrate that the first and second switch domains described herein can be in different orientations with respect to the antigen binding member and the intracellular binding member.
  • Other RCAR configurations are further described herein.
  • Figure 54 shows that the proliferation of CAR-expressing, transduced T cells is enhanced by low doses of RADOOl in a cell culture system.
  • CARTs were co-cultured with Nalm-6 cells in the presence of different concentrations of RADOOl.
  • the number of CAR- positive CD3-positive T cells (black) and total T cells (gray) was assessed after 4 days of co- culture.
  • Figure 55 depicts tumor growth measurements of NALM6-luc cells with daily RADOOl dosing at 0.3, 1, 3, and 10 mg/kg (mpk) or vehicle dosing. Circles denote the vehicle; squares denote the 10 mg/kg dose of RADOOl; triangles denote the 3 mg/kg dose of RADOOl, inverted triangles denote the 1 mg/kg dose of RADOOl; and diamonds denote the 0.3 mg/kg dose of RADOOl.
  • Figures 56A and 56B show pharmacokinetic curves showing the amount of RADOOl in the blood of NSG mice with NALM6 tumors.
  • FIG. 56A shows day 0 PK following the first dose of RADOOl.
  • FIG. 56B shows Day 14 PK following the final RADOOl dose.
  • Diamonds denote the 10 mg/kg dose of RADOOl; squares denote the 1 mg/kg dose of RADOOl; triangles denote the 3 mg/kg dose of RADOOl; and x's denote the 10 mg/kg dose of RADOOl.
  • Figures 57 A and 57B show in vivo proliferation of humanized CD 19 CART cells with and without RADOOl dosing. Low doses of RADOOl (0.003 mg/kg) daily lead to an enhancement in CAR T cell proliferation, above the normal level of huCAR19 proliferation.
  • Figures 57A shows CD4 + CAR T cells;
  • FIG. 57B shows CD8 + CAR T cells.
  • Circles denote PBS; squares denote huCTL019; triangles denote huCTL019 with 3 mg/kg RADOOl; inverted triangles denote huCTL019 with 0.3 mg/kg RADOOl; diamonds denote huCTL019 with 0.03 mg/kg RADOOl ; and circles denote huCTL019 with 0.003 mg/kg RADOOl .
  • Figure 58 is a graph showing HL-60-luc xenograft AML disease progression.
  • Blue circles mice treated with lOOul of PBS via the tail vein; red squares: mice treated with CD19 CAR T cells; green triangles: mice treated with CD33-1 CAR transduced T cells; inverted purple triangles: mice treated with CD33-2 CAR transduced T cells; orange diamonds: mice treated with CD33-4 CAR transduced T cells; black squares: mice treated with CD33-5 CAR transduced T cells; brown triangles: mice treated with CD33-6 CAR transduced T cells; dark blue circles: mice treated with CD33-7 CAR transduced T cells; and inverted dark purple triangles: mice treated with CD33-9 CAR transduced T cells.
  • an element means one element or more than one element.
  • CAR Chimeric Antigen Receptor
  • a recombinant polypeptide construct comprising at least an extracellular antigen binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to herein as "an intracellular signaling domain") comprising a functional signaling domain derived from a stimulatory molecule as defined below.
  • the domains in the CAR polypeptide construct are in the same polypeptide chain, e.g., comprise a chimeric fusion protein.
  • the domains in the CAR polypeptide construct are not contiguous with each other, e.g., are in different polypeptide chains, e.g., as provided in an RCAR as described herein.
  • the stimulatory molecule of the CAR is the zeta chain associated with the T cell receptor complex.
  • the cytoplasmic signaling domain comprises a primary signaling domain (e.g., a primary signaling domain of CD3-zeta).
  • the cytoplasmic signaling domain further comprises one or more functional signaling domains derived from at least one costimulatory molecule as defined below.
  • the costimulatory molecule is chosen from 4-1BB (i.e., CD137), CD27, ICOS, and/or CD28.
  • the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a stimulatory molecule. In one aspect, the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising a functional signaling domain derived from a co- stimulatory molecule and a functional signaling domain derived from a stimulatory molecule.
  • the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising two functional signaling domains derived from one or more co-stimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule.
  • the CAR comprises a chimeric fusion protein comprising an extracellular antigen recognition domain, a transmembrane domain and an intracellular signaling domain comprising at least two functional signaling domains derived from one or more co-stimulatory molecule(s) and a functional signaling domain derived from a stimulatory molecule.
  • the CAR comprises an optional leader sequence at the amino-terminus (N-ter) of the CAR fusion protein.
  • the CAR further comprises a leader sequence at the N-terminus of the extracellular antigen recognition domain, wherein the leader sequence is optionally cleaved from the antigen recognition domain (e.g., aa scFv) during cellular processing and localization of the CAR to the cellular membrane.
  • the antigen recognition domain e.g., aa scFv
  • a CAR that comprises an antigen binding domain e.g., a scFv, a single domain antibody, or TCR (e.g., a TCR alpha binding domain or TCR beta binding domain)) that targets a specific tumor marker X, wherein X can be a tumor marker as described herein, is also referred to as XCAR.
  • a CAR that comprises an antigen binding domain that targets CD33 is referred to as CD33CAR.
  • the CAR can be expressed in any cell, e.g., an immune effector cell as described herein (e.g., a T cell or an NK cell).
  • signaling domain refers to the functional portion of a protein which acts by transmitting information within the cell to regulate cellular activity via defined signaling pathways by generating second messengers or functioning as effectors by responding to such messengers.
  • CD33 refers to the Cluster of Differentiation 33 protein, which is an antigenic determinant detectable on leukemia cells as well on normal precursor cells of the myeloid lineage.
  • the human and murine amino acid and nucleic acid sequences can be found in a public database, such as GenBank, UniProt and Swiss-Prot.
  • the amino acid sequence of human CD33 can be found as UniProt/Swiss-Prot Accession No.
  • CD33 includes proteins comprising mutations, e.g., point mutations, fragments, insertions, deletions and splice variants of full length wild- type CD33.
  • antibody refers to a protein, or polypeptide sequence derived from an immunoglobulin molecule which specifically binds with an antigen.
  • Antibodies can be polyclonal or monoclonal, multiple or single chain, or intact
  • immunoglobulins may be derived from natural sources or from recombinant sources.
  • Antibodies can be tetramers of immunoglobulin molecules.
  • antibody fragment refers to at least one portion of an intact antibody, or recombinant variants thereof, and refers to the antigen binding domain, e.g., an antigenic determining variable region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen.
  • antibody fragments include, but are not limited to, Fab, Fab', F(ab') 2 , and Fv fragments, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, and multi- specific molecules formed from antibody fragments ⁇ such as a bivalent fragment comprising two or more, e.g., two, Fab fragments linked by a disulfide brudge at the hinge region, or two or more, e.g., two isolated CDR or other epitope binding fragments of an antibody linked.
  • An antibody fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005).
  • Antibody fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3)(see U.S. Patent No.: 6,703,199, which describes fibronectin polypeptide minibodies).
  • Fn3 fibronectin type III
  • scFv refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived.
  • an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.
  • CDR complementarity determining region
  • HCDR1, HCDR2, and HCDR3 three CDRs in each heavy chain variable region
  • LCDRl, LCDR2, and LCDR3 three CDRs in each light chain variable region
  • the precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed.
  • the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDRl), 50-56 (LCDR2), and 89-97 (LCDR3).
  • the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the VL are numbered 26-32 (LCDRl), 50-52 (LCDR2), and 91-96 (LCDR3).
  • the CDRs correspond to the amino acid residues that are part of a Kabat CDR, a Chothia CDR, or both.
  • the CDRs correspond to amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in a VH, e.g., a mammalian VH, e.g., a human VH; and amino acid residues 24-34 (LCDRl), 50-56 (LCDR2), and 89-97 (LCDR3) in a VL, e.g., a mammalian VL, e.g., a human VL.
  • the portion of the CAR composition of the invention comprising an antibody or antibody fragment thereof may exist in a variety of forms, for example, where the antigen binding domain is expressed as part of a polypeptide chain including, for example, a single domain antibody fragment (sdAb), a single chain antibody (scFv), or e.g., a humanized or human antibody (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci.
  • sdAb single domain antibody fragment
  • scFv single chain antibody
  • the antigen binding domain of a CAR composition of the invention comprises an antibody fragment.
  • the CAR comprises an antibody fragment that comprises a scFv.
  • binding domain or "antibody molecule” refers to a protein, e.g., an immunoglobulin chain or fragment thereof, comprising at least one
  • an antibody molecule is a multispecific antibody molecule, e.g., it comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope.
  • a multispecific antibody molecule is a bispecific antibody molecule.
  • a bispecific antibody has specificity for no more than two antigens.
  • a bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope.
  • antibody heavy chain refers to the larger of the two types of polypeptide chains present in antibody molecules in their naturally occurring conformations, and which normally determines the class to which the antibody belongs.
  • antibody light chain refers to the smaller of the two types of polypeptide chains present in antibody molecules in their naturally occurring conformations. Kappa ( ⁇ ) and lambda ( ⁇ ) light chains refer to the two major antibody light chain isotypes.
  • recombinant antibody refers to an antibody which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage or yeast expression system.
  • the term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using recombinant DNA or amino acid sequence technology which is available and well known in the art.
  • antigen or "Ag” refers to a molecule that provokes an immune response.
  • This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both.
  • any macromolecule including virtually all proteins or peptides, can serve as an antigen.
  • antigens can be derived from recombinant or genomic DNA.
  • any DNA which comprises a nucleotide sequences or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an "antigen" as that term is used herein.
  • an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to encode polypeptides that elicit the desired immune response.
  • an antigen need not be encoded by a "gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample, or might be macromolecule besides a polypeptide. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a fluid with other biological components.
  • anti-tumor effect refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, decrease in tumor cell proliferation, decrease in tumor cell survival, or
  • an "anti-tumor effect" can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies of the invention in prevention of the occurrence of tumor in the first place.
  • anti-cancer effect refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of cancer cells, a decrease in the number of metastases, an increase in life expectancy, decrease in cancer cell proliferation, decrease in cancer cell survival, or amelioration of various physiological symptoms associated with the cancerous condition.
  • An "anti-cancer effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies in prevention of the occurrence of cancer in the first place.
  • anti-tumor effect refers to a biological effect which can be manifested by various means, including but not limited to, e.g., a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, or a decrease in tumor cell survival.
  • autologous refers to any material derived from the same individual to whom it is later to be re-introduced into the individual.
  • allogeneic refers to any material derived from a different animal of the same species as the individual to whom the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical. In some aspects, allogeneic material from individuals of the same species may be sufficiently unlike genetically to interact antigenically.
  • xenogeneic refers to a graft derived from an animal of a different species.
  • an apheresis sample refers to a sample obtained using apheresis.
  • combination refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present invention and a combination partner (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a combination partner e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”
  • the single components may be packaged in a kit or separately.
  • One or both of the components e.g., powders or liquids
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of the present invention and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of the present invention and a combination partner are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • cancer refers to a disease characterized by the rapid and uncontrolled growth of aberrant cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body. Examples of various cancers are described herein and include but are not limited to, breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer and the like.
  • tumor and “cancer” are used interchangeably herein, e.g., both terms encompass solid and liquid, e.g., diffuse or circulating, tumors. As used herein, the term “cancer” or “tumor” includes premalignant, as well as malignant cancers and tumors.
  • “Derived from” indicates a relationship between a first and a second molecule. It generally refers to structural similarity between the first molecule and a second molecule and does not connotate or include a process or source limitation on a first molecule that is derived from a second molecule. For example, in the case of an intracellular signaling domain that is derived from a CD3zeta molecule, the intracellular signaling domain retains sufficient CD3zeta structure such that is has the required function, namely, the ability to generate a signal under the appropriate conditions.
  • disease associated with expression of CD33 includes but is not limited to, a disease associated with a cell which expresses CD33 (e.g., wild-type or mutant CD33) or condition associated with a cell which expresses CD33 (e.g., wild- type or mutant CD33) including, e.g., a proliferative disease such as a cancer or malignancy or a precancerous condition such as a myelodysplasia, a myelodysplasia syndrome or a preleukemia; or a noncancer related indication associated with a cell which expresses CD33 (e.g., wild-type or mutant CD33).
  • a proliferative disease such as a cancer or malignancy
  • a precancerous condition such as a myelodysplasia, a myelodysplasia syndrome or a preleukemia
  • noncancer related indication associated with a cell which expresses CD33 (e.g., wild-type or mutant CD
  • a disease associated with expression of CD33 may include a condition associated with a cell which do not presently express CD33, e.g., because CD33 expression has been downregulated, e.g., due to treatment with a molecule targeting
  • a cancer associated with expression of CD33 is a hematological cancer.
  • a hematological cancer includes but is not limited to acute myeloid leukemia (AML), myelodysplasia and myelodysplasia syndrome, myelofibrosis and myeloproliferative neoplasms, acute lymphoid leukemia (ALL), hairy cell leukemia, Prolymphocyte leukemia, chronic myeloid leukemia (CML), Blastic plasmacytoid dendritic cell neoplasm, and the like.
  • AML acute myeloid leukemia
  • ALL myelodysplasia and myelodysplasia syndrome
  • myelofibrosis and myeloproliferative neoplasms acute lymphoid leukemia (ALL), hairy cell leukemia, Prolymphocyte leukemia, chronic myeloid leukemia (CML), Blastic plasmacytoid dendritic cell neoplasm,
  • CD33 e.g., wild- type or mutant CD33
  • Further disease associated with expression of CD33 include, but are not limited to, e.g., atypical and/or non-classical cancers, malignancies, precancerous conditions or proliferative diseases associated with expression of CD33 (e.g., wild-type or mutant CD33).
  • Non-cancer related indications associated with expression of CD33 may also be included.
  • a non-cancer related indication associated with expression of CD33 includes but is not limited to, e.g., autoimmune disease, (e.g., lupus), inflammatory disorders (allergy and asthma) and transplantation.
  • the tumor antigen-expressing cell expresses, or at any time expressed, mRNA encoding the tumor antigen.
  • the tumor antigen -expressing cell produces the tumor antigen protein (e.g., wild-type or mutant), and the tumor antigen protein may be present at normal levels or reduced levels.
  • the tumor antigen -expressing cell produced detectable levels of a tumor antigen protein at one point, and subsequently produced substantially no detectable tumor antigen protein.
  • conservative sequence modifications refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antibody fragment of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative substitutions are ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art.
  • amino acids with basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic acid, glutamic acid
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan
  • nonpolar side chains e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • beta-branched side chains e.g., threonine, valine, isoleucine
  • aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine.
  • one or more amino acid residues within a CAR of the invention can be replaced with other amino acid residues from the same side chain family and the altered CAR can be tested using the functional assays described herein.
  • stimulation refers to a primary response induced by binding of a stimulatory molecule (e.g., a TCR/CD3 complex) with its cognate ligand thereby mediating a signal transduction event, such as, but not limited to, signal transduction via the TCR/CD3 complex.
  • a stimulatory molecule e.g., a TCR/CD3 complex
  • signal transduction event such as, but not limited to, signal transduction via the TCR/CD3 complex.
  • Stimulation can mediate altered expression of certain molecules, such as
  • the term "stimulatory molecule,” refers to a molecule expressed by a T cell that provides the primary cytoplasmic signaling sequence(s) that regulate primary activation of the TCR complex in a stimulatory way for at least some aspect of the T cell signaling pathway.
  • the primary signal is initiated by, for instance, binding of a TCR/CD3 complex with an MHC molecule loaded with peptide, and which leads to mediation of a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like.
  • a primary cytoplasmic signaling sequence (also referred to as a "primary signaling domain") that acts in a stimulatory manner may contain a signaling motif which is known as immunoreceptor tyrosine- based activation motif or IT AM.
  • IT AM immunoreceptor tyrosine- based activation motif
  • Examples of an IT AM containing primary cytoplasmic signaling sequence that is of particular use in the invention includes, but is not limited to, those derived from TCR zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta , CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (also known as "ICOS”), FcsRI and CD66d, DAP10 and DAP12.
  • the intracellular signaling domain in any one or more CARs of the invention comprises an intracellular signaling sequence, e.g., a primary signaling sequence of CD3-zeta.
  • the primary signaling sequence of CD3-zeta is the sequence provided as SEQ ID NO:9, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like.
  • the primary signaling sequence of CD3-zeta is the sequence as provided in SEQ ID NO: 10, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like.
  • an immune system cell such as an accessory cell (e.g., a B-cell, a dendritic cell, and the like) that displays a foreign antigen complexed with major histocompatibility complexes (MHC's) on its surface.
  • MHC's major histocompatibility complexes
  • T-cells may recognize these complexes using their T-cell receptors (TCRs).
  • APCs process antigens and present them to T-cells.
  • intracellular signaling domain refers to an intracellular portion of a molecule.
  • the intracellular signal domain transduces the effector function signal and directs the cell to perform a specialized function. While the entire intracellular signaling domain can be employed, in many cases it is not necessary to use the entire chain. To the extent that a truncated portion of the intracellular signaling domain is used, such truncated portion may be used in place of the intact chain as long as it transduces the effector function signal.
  • intracellular signaling domain is thus meant to include any truncated portion of the intracellular signaling domain sufficient to transduce the effector function signal.
  • the intracellular signaling domain can generate a signal that promotes an immune effector function of the CAR containing cell, e.g., a CART cell or CAR-expressing NK cell.
  • immune effector function e.g., in a CART cell or CAR-expressing NK cell, include cytolytic activity and helper activity, including the secretion of cytokines.
  • the intracellular signaling domain can comprise a primary intracellular signaling domain.
  • Exemplary primary intracellular signaling domains include those derived from the molecules responsible for primary stimulation, or antigen dependent simulation.
  • the intracellular signaling domain can comprise a costimulatory intracellular domain.
  • Exemplary costimulatory intracellular signaling domains include those derived from molecules responsible for costimulatory signals, or antigen independent stimulation.
  • a primary intracellular signaling domain can comprise a cytoplasmic sequence of a T cell receptor
  • a costimulatory intracellular signaling domain can comprise cytoplasmic sequence from co-receptor or costimulatory molecule.
  • a primary intracellular signaling domain can comprise a signaling motif which is known as an immunoreceptor tyrosine-based activation motif or IT AM.
  • IT AM immunoreceptor tyrosine-based activation motif
  • ⁇ containing primary cytoplasmic signaling sequences include, but are not limited to, those derived from CD3 zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (also known as "ICOS”), FcsRI and CD66d, DAP10 and DAP12.
  • zeta or alternatively “zeta chain”, “CD3-zeta” or “TCR-zeta” is defined as the protein provided as GenBan Acc. No. BAG36664.1, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like, and a "zeta stimulatory domain” or alternatively a "CD3-zeta stimulatory domain” or a “TCR-zeta stimulatory domain” is defined as the amino acid residues from the cytoplasmic domain of the zeta chain that are sufficient to functionally transmit an initial signal necessary for T cell activation.
  • the cytoplasmic domain of zeta comprises residues 52 through 164 of GenBank Acc. No.
  • the "zeta stimulatory domain” or a "CD3-zeta stimulatory domain” is the sequence provided as SEQ ID NO:9. In one aspect, the "zeta stimulatory domain” or a “CD3-zeta stimulatory domain” is the sequence provided as SEQ ID NO: 10.
  • costimulatory molecule refers to the cognate binding partner on a T cell that specifically binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation.
  • Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an efficient immune response.
  • Costimulatory molecules include, but are not limited to an MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1
  • CDl la/CD18 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDl ld, ITGAE, CD103, ITGAL, CDl la, LFA-1, ITGAM, CDl lb, ITGAX, CDl lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, NKG2C, TNFR2, TRANCE/RANKL, DNAM1 (CD226),
  • a costimulatory intracellular signaling domain refers to the intracellular portion of a costimulatory molecule.
  • the intracellular signaling domain can comprise the entire intracellular portion, or the entire native intracellular signaling domain, of the molecule from which it is derived, or a functional fragment thereof.
  • 4- IBB refers to a member of the TNFR superfamily with an amino acid sequence provided as GenBank Acc. No. AAA62478.2, or the equivalent residues from a non- human species, e.g., mouse, rodent, monkey, ape and the like; and a "4-1BB costimulatory domain” is defined as amino acid residues 214-255 of GenBank accno. AAA62478.2, or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like.
  • the "4- IBB costimulatory domain” is the sequence provided as SEQ ID NO:7 or the equivalent residues from a non-human species, e.g., mouse, rodent, monkey, ape and the like.
  • Immuno effector cell refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response.
  • immune effector cells include T cells, e.g., alpha/beta T cells and gamma/delta T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, mast cells, and myeloic-derived phagocytes.
  • Immuno effector function or immune effector response refers to function or response, e.g., of an immune effector cell, that enhances or promotes an immune attack of a target cell.
  • an immune effector function or response refers a property of a T or NK cell that promotes killing or the inhibition of growth or proliferation, of a target cell.
  • primary stimulation and co-stimulation are examples of immune effector function or response.
  • effector function refers to a specialized function of a cell.
  • Effector function of a T cell may be cytolytic activity or helper activity including the secretion of cytokines.
  • encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
  • a gene, cDNA, or RNA encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system.
  • Both the coding strand the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.
  • the phrase nucleotide sequence that encodes a protein or a RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).
  • an effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result.
  • endogenous refers to any material from or produced inside an organism, cell, tissue or system.
  • exogenous refers to any material introduced from or produced outside an organism, cell, tissue or system.
  • expression refers to the transcription and/or translation of a particular nucleotide sequence driven by a promoter.
  • transfer vector refers to a composition of matter which comprises an isolated nucleic acid and which can be used to deliver the isolated nucleic acid to the interior of a cell.
  • Numerous vectors are known in the art including, but not limited to, linear
  • transfer vector includes an autonomously replicating plasmid or a virus.
  • the term should also be construed to further include non-plasmid and non-viral compounds which facilitate transfer of nucleic acid into cells, such as, for example, a polylysine compound, liposome, and the like.
  • viral transfer vectors include, but are not limited to, adenoviral vectors, adeno-associated virus vectors, retroviral vectors, lenti viral vectors, and the like.
  • expression vector refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed.
  • An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system.
  • Expression vectors include all those known in the art, including cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.
  • lentivirus refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect non-dividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses.
  • lentiviral vector refers to a vector derived from at least a portion of a lentivirus genome, including especially a self-inactivating lentiviral vector as provided in Milone et al., Mol. Ther. 17(8): 1453-1464 (2009).
  • Other examples of lentivirus vectors that may be used in the clinic include but are not limited to, e.g., the LENTIVECTOR® gene delivery technology from Oxford BioMedica, the LENTIMAXTM vector system from Lentigen and the like. Nonclinical types of lentiviral vectors are also available and would be known to one skilled in the art.
  • homologous refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules.
  • two nucleic acid molecules such as, two DNA molecules or two RNA molecules
  • polypeptide molecules between two polypeptide molecules.
  • a subunit position in both of the two molecules is occupied by the same monomeric subunit; e.g., if a position in each of two DNA molecules is occupied by adenine, then they are homologous or identical at that position.
  • the homology between two sequences is a direct function of the number of matching or homologous positions; e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (e.g., 9 of 10), are matched or homologous, the two sequences are 90% homologous.
  • Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies and antibody fragments thereof are human immunoglobulins (recipient antibody or antibody fragment) in which residues from a complementary-determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity, and capacity.
  • CDR complementary-determining region
  • Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues.
  • a humanized antibody/antibody fragment can comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences.
  • the humanized antibody or antibody fragment thereof will comprise substantially all of at least one, and typically two, variable domains, in which all or
  • substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or a significant portion of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody or antibody fragment can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • Fully human refers to an immunoglobulin, such as an antibody or antibody fragment, where the whole molecule is of human origin or consists of an amino acid sequence identical to a human form of the antibody or immunoglobulin.
  • isolated means altered or removed from the natural state.
  • a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.”
  • An isolated nucleic acid or protein can exist in substantially purified form, or can exist in a non-native environment such as, for example, a host cell.
  • A refers to adenosine
  • C refers to cytosine
  • G refers to guanosine
  • T refers to thymidine
  • U refers to uridine.
  • operably linked refers to functional linkage between a regulatory sequence and a heterologous nucleic acid sequence resulting in expression of the latter.
  • a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence.
  • a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence.
  • Operably linked DNA sequences can be contiguous with each other and, e.g., where necessary to join two protein coding regions, are in the same reading frame.
  • parenteral administration of an immunogenic composition includes, e.g., subcutaneous (s.c), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection,
  • nucleic acid or “polynucleotide” refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double- stranded form.
  • nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.
  • a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated.
  • degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).
  • peptide refers to a compound comprised of amino acid residues covalently linked by peptide bonds.
  • a protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein's or peptide's sequence.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. "Polypeptides" include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes a natural peptide, a recombinant peptide, or a combination thereof.
  • promoter refers to a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence.
  • promoter/regulatory sequence refers to a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product.
  • the promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue specific manner.
  • constitutive promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.
  • inducible promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell substantially only when an inducer which corresponds to the promoter is present in the cell.
  • tissue-specific promoter refers to a nucleotide sequence which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.
  • cancer associated antigen or “tumor antigen” interchangeably refers to a molecule (typically a protein, carbohydrate or lipid) that is expressed on the surface of a cancer cell, either entirely or as a fragment (e.g., MHC/peptide), and which is useful for the preferential targeting of a pharmacological agent to the cancer cell.
  • a tumor antigen is a marker expressed by both normal cells and cancer cells, e.g., a lineage marker, e.g., CD19 on B cells.
  • a tumor antigen is a cell surface molecule that is overexpressed in a cancer cell in comparison to a normal cell, for instance, 1- fold over expression, 2-fold overexpression, 3-fold overexpression or more in comparison to a normal cell.
  • a tumor antigen is a cell surface molecule that is
  • the CARs of the present invention includes CARs comprising an antigen binding domain (e.g., antibody or antibody fragment) that binds to a tumor antigen binding domain (e.g., antibody or antibody fragment) that binds to a tumor antigen binding domain (e.g., antibody or antibody fragment) that binds to a tumor antigen binding domain (e.g., antibody or antibody fragment) that binds to a tumor antigen binding domain (e.g., antibody or antibody fragment) that binds to a
  • MHC presented peptide.
  • peptides derived from endogenous proteins fill the pockets of Major histocompatibility complex (MHC) class I molecules, and are recognized by T cell receptors (TCRs) on CD8 + T lymphocytes.
  • TCRs T cell receptors
  • the MHC class I complexes are constitutively expressed by all nucleated cells.
  • virus- specific and/or tumor- specific peptide/MHC complexes represent a unique class of cell surface targets for immunotherapy.
  • TCR-like antibodies targeting peptides derived from viral or tumor antigens in the context of human leukocyte antigen (HLA)-Al or HLA-A2 have been described (see, e.g., Sastry et al., J Virol.
  • TCR-like antibody can be identified from screening a library, such as a human scFv phage displayed library.
  • tumor-supporting antigen or “cancer-supporting antigen”
  • a molecule typically a protein, carbohydrate or lipid
  • a cell that is, itself, not cancerous, but supports the cancer cells, e.g., by promoting their growth or survival e.g., resistance to immune cells.
  • exemplary cells of this type include stromal cells and myeloid-derived suppressor cells (MDSCs).
  • MDSCs myeloid-derived suppressor cells
  • flexible polypeptide linker or "linker” as used in the context of a scFv refers to a peptide linker that consists of amino acids such as glycine and/or serine residues used alone or in combination, to link variable heavy and variable light chain regions together.
  • the flexible polypeptide linkers include, but are not limited to, (Gly4 Ser) 4 (SEQ ID NO:27) or (Gly4 Ser)s (SEQ ID NO:26).
  • the linkers include multiple repeats of (Gly2Ser),
  • a 5' cap (also termed an RNA cap, an RNA 7-methylguanosine cap or an RNA m G cap) is a modified guanine nucleotide that has been added to the "front" or 5' end of a eukaryotic messenger RNA shortly after the start of transcription.
  • the 5' cap consists of a terminal group which is linked to the first transcribed nucleotide. Its presence is critical for recognition by the ribosome and protection from RNases. Cap addition is coupled to transcription, and occurs co-transcriptionally, such that each influences the other.
  • the 5' end of the mRNA being synthesized is bound by a cap- synthesizing complex associated with RNA polymerase. This enzymatic complex catalyzes the chemical reactions that are required for mRNA capping. Synthesis proceeds as a multi-step biochemical reaction.
  • the capping moiety can be modified to modulate functionality of mRNA such as its stability or efficiency of translation.
  • in vitro transcribed RNA refers to RNA, preferably mRNA, that has been synthesized in vitro.
  • the in vitro transcribed RNA is generated from an in vitro transcription vector.
  • the in vitro transcription vector comprises a template that is used to generate the in vitro transcribed RNA.
  • poly(A) is a series of adenosines attached by polyadenylation to the mRNA.
  • the polyA is between 50 and 5000 (SEQ ID NO: 30), preferably greater than 64, more preferably greater than 100, most preferably greater than 300 or 400.
  • poly(A) sequences can be modified chemically or enzymatically to modulate mRNA functionality such as localization, stability or efficiency of translation.
  • polyadenylation refers to the covalent linkage of a polyadenylyl moiety, or its modified variant, to a messenger RNA molecule.
  • mRNA messenger RNA
  • the 3' poly(A) tail is a long sequence of adenine nucleotides (often several hundred) added to the pre-mRNA through the action of an enzyme, polyadenylate polymerase.
  • poly(A) tail is added onto transcripts that contain a specific sequence, the polyadenylation signal.
  • Polyadenylation is also important for transcription termination, export of the mRNA from the nucleus, and translation. Polyadenylation occurs in the nucleus immediately after transcription of DNA into RNA, but additionally can also occur later in the cytoplasm.
  • the mRNA chain is cleaved through the action of an endonuclease complex associated with RNA polymerase.
  • the cleavage site is usually characterized by the presence of the base sequence AAUAAA near the cleavage site.
  • adenosine residues are added to the free 3' end at the cleavage site.
  • transient refers to expression of a non-integrated transgene for a period of hours, days or weeks, wherein the period of time of expression is less than the period of time for expression of the gene if integrated into the genome or contained within a stable plasmid replicon in the host cell.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a CAR of the invention).
  • the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient.
  • the terms “treat”, “treatment” and “treating” -refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
  • signal transduction pathway refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of a cell.
  • cell surface receptor includes molecules and complexes of molecules capable of receiving a signal and transmitting signal across the membrane of a cell.
  • subject is intended to include living organisms in which an
  • immune response can be elicited (e.g., mammals, human).
  • substantially purified cell refers to a cell that is essentially free of other cell types.
  • a substantially purified cell also refers to a cell which has been separated from other cell types with which it is normally associated in its naturally occurring state.
  • a population of substantially purified cells refers to a homogenous population of cells. In other instances, this term refers simply to cell that have been separated from the cells with which they are naturally associated in their natural state.
  • the cells are cultured in vitro. In other aspects, the cells are not cultured in vitro.
  • terapéutica means a treatment. A therapeutic effect is obtained by reduction, suppression, remission, or eradication of a disease state.
  • prophylaxis means the prevention of or protective treatment for a disease or disease state.
  • tumor antigen or “hyperproliferative disorder antigen” or “antigen associated with a hyperproliferative disorder” refers to antigens that are common to specific hyperproliferative disorders.
  • the hyperproliferative disorder or “antigen associated with a hyperproliferative disorder” refers to antigens that are common to specific hyperproliferative disorders.
  • hyperproliferative disorder antigens of the present invention are derived from, cancers including but not limited to primary or metastatic melanoma, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemias, uterine cancer, cervical cancer, bladder cancer, kidney cancer and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and the like.
  • cancers including but not limited to primary or metastatic melanoma, thymoma, lymphoma, sarcoma, lung cancer, liver cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, leukemias, uterine cancer, cervical cancer, bladder cancer, kidney cancer and adenocarcinomas such as breast cancer, prostate cancer, ovarian cancer, pancreatic cancer, and the like.
  • transfected or “transformed” or “transduced” refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell.
  • a “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid.
  • the cell includes the primary subject cell and its progeny.
  • the term “specifically binds,” refers to an antibody, or a ligand, which recognizes and binds with a cognate binding partner (e.g., a stimulatory and/or costimulatory molecule present on a T cell) protein present in a sample, but which antibody or ligand does not substantially recognize or bind other molecules in the sample.
  • a cognate binding partner e.g., a stimulatory and/or costimulatory molecule present on a T cell
  • RCAR Registered chimeric antigen receptor
  • an RCAR refers to a set of polypeptides, typically two in the simplest embodiments, which when in an immune effector cell, provides the cell with specificity for a target cell, typically a cancer cell, and with intracellular signal generation.
  • an RCAR comprises at least an extracellular antigen binding domain, a transmembrane domain and a cytoplasmic signaling domain (also referred to herein as "an intracellular signaling domain”) comprising a functional signaling domain derived from a stimulatory molecule and/or costimulatory molecule as defined herein in the context of a CAR molecule.
  • the RCAR includes a dimerization switch that, upon the presence of a dimerization molecule, can couple the polypeptides to one another, e.g., can couple an antigen binding domain to an intracellular signaling domain.
  • the RCAR is expressed in a cell (e.g., an immune effector cell) as described herein, e.g., an RCAR-expressing cell (also referred to herein as "RCARX cell").
  • the RCARX cell is a T cell, and is referred to as a RCART cell.
  • the RCARX cell is an NK cell, and is referred to as a RCARN cell.
  • the RCAR can provide the RCAR- expressing cell with specificity for a target cell, typically a cancer cell, and with regulatable intracellular signal generation or proliferation, which can optimize an immune effector property of the RCAR-expressing cell.
  • an RCAR cell relies at least in part, on an antigen binding domain to provide specificity to a target cell that comprises the antigen bound by the antigen binding domain.
  • Membrane anchor or “membrane tethering domain”, as that term is used herein, refers to a polypeptide or moiety, e.g., a myristoyl group, sufficient to anchor an extracellular or intracellular domain to the plasma membrane.
  • Switch domain refers to an entity, typically a polypeptide-based entity, that, in the presence of a dimerization molecule, associates with another switch domain. The association results in a functional coupling of a first entity linked to, e.g., fused to, a first switch domain, and a second entity linked to, e.g., fused to, a second switch domain.
  • a first and second switch domain are collectively referred to as a dimerization switch.
  • the first and second switch domains are the same as one another, e.g., they are polypeptides having the same primary amino acid sequence, and are referred to collectively as a homodimerization switch. In embodiments, the first and second switch domains are different from one another, e.g., they are polypeptides having different primary amino acid sequences, and are referred to collectively as a heterodimerization switch. In embodiments, the switch is intracellular. In embodiments, the switch is extracellular. In embodiments, the switch domain is a polypeptide-based entity, e.g., FKBP or FRB-based, and the dimerization molecule is small molecule, e.g., a rapalogue.
  • the switch domain is a polypeptide-based entity, e.g., an scFv that binds a myc peptide
  • the dimerization molecule is a polypeptide, a fragment thereof, or a multimer of a polypeptide, e.g., a myc ligand or multimers of a myc ligand that bind to one or more myc scFvs.
  • the switch domain is a polypeptide-based entity, e.g., myc receptor
  • the dimerization molecule is an antibody or fragments thereof, e.g., myc antibody.
  • RCAR refers to a molecule that promotes the association of a first switch domain with a second switch domain.
  • the dimerization molecule does not naturally occur in the subject, or does not occur in concentrations that would result in significant dimerization.
  • the dimerization molecule is a small molecule, e.g., rapamycin or a rapalogue, e.g, RAD001.
  • bioequivalent refers to an amount of an agent other than the reference compound (e.g., RAD001), required to produce an effect equivalent to the effect produced by the reference dose or reference amount of the reference compound ( e.g., RAD001).
  • the effect is the level of mTOR inhibition, e.g., as measured by P70 S6 kinase inhibition, e.g., as evaluated in an in vivo or in vitro assay, e.g., as measured by an assay described herein, e.g., the Boulay assay, or measurement of phosphorylated S6 levels by western blot.
  • the effect is alteration of the ratio of PD-1 positive/PD-1 negative immune effector cells, e.g., T cells or NK cells, as measured by cell sorting.
  • a bioequivalent amount or dose of an mTOR inhibitor is the amount or dose that achieves the same level of P70 S6 kinase inhibition as does the reference dose or reference amount of a reference compound.
  • a bioequivalent amount or dose of an mTOR inhibitor is the amount or dose that achieves the same level of alteration in the ratio of PD-1 positive/PD-1 negative immune effector cells, e.g., T cells or NK cells as does the reference dose or reference amount of a reference compound.
  • low, immune enhancing, dose when used in conjuction with an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, e.g., RAD001 or rapamycin, or a catalytic mTOR inhibitor, refers to a dose of mTOR inhibitor that partially, but not fully, inhibits mTOR activity, e.g., as measured by the inhibition of P70 S6 kinase activity. Methods for evaluating mTOR activity, e.g., by inhibition of P70 S6 kinase, are discussed herein. The dose is insufficient to result in complete immune suppression but is sufficient to enhance the immune response.
  • an mTOR inhibitor e.g., an allosteric mTOR inhibitor, e.g., RAD001 or rapamycin, or a catalytic mTOR inhibitor
  • the low, immune enhancing, dose of mTOR inhibitor results in a decrease in the number of PD-1 positive immune effector cells, e.g., T cells or NK cells and/or an increase in the number of PD-1 negative immune effector cells, e.g., T cells or NK cells, or an increase in the ratio of PD-1 negative immune effector cells (e.g., T cells or NK cells) /PD-1 positive immune effector cells (e.g., T cells or NK cells).
  • the low, immune enhancing, dose of mTOR inhibitor results in an increase in the number of naive T cells.
  • the low, immune enhancing, dose of mTOR inhibitor results in one or more of the following: an increase in the expression of one or more of the following markers: CD62L lg , CD127 high , CD27 + , and BCL2, e.g., on memory T cells, e.g., memory T cell precursors;
  • KLRG1 a decrease in the expression of KLRG1, e.g., on memory T cells, e.g., memory T cell precursors;
  • an increase in the number of memory T cell precursors e.g., cells with any one or combination of the following characteristics: increased CD62L hlgh , increased CD127 hlgh , increased CD27 + , decreased KLRG1, and increased BCL2;
  • any of the changes described above occurs, e.g., at least transiently, e.g., as compared to a non-treated subject.
  • Refractory refers to a disease, e.g., cancer, that does not respond to a treatment.
  • a refractory cancer can be resistant to a
  • refractory cancer can become resistant during a treatment.
  • a refractory cancer is
  • Relapsed or a “relapse” as used herein refers to the reappearance of a disease
  • the period of responsiveness may involve the level of cancer cells falling below a certain threshold, e.g., below 20%, 1%, 10%, 5%, 4%, 3%, 2%, or 1%.
  • the reappearance may involve the level of cancer cells rising above a certain threshold, e.g., above 20%, 1%, 10%, 5%, 4%, 3%, 2%, or 1%.
  • CAR chimeric antigen receptors
  • the invention provides a number of chimeric antigen receptors (CAR) comprising an antibody or antibody fragment engineered for specific binding to a CD33 protein or fragments thereof.
  • CAR chimeric antigen receptors
  • the invention provides a cell (e.g., an immune effector cell, e.g., T cell or NK cell) engineered to express a CAR, wherein the cell (e.g., "CART") exhibits an antitumor property.
  • a cell is transformed with the CAR and the or at least part of the CAR is expressed on the cell surface.
  • the cell e.g., immune effector cell, e.g., T cell or NK cell
  • the viral vector is a retroviral vector. In some embodiments, the viral vector is a lentiviral vector. In some such embodiments, the cell may stably express the CAR. In another embodiment, the cell (e.g., immune effector cell, e.g., T cell or NK cell) is transfected with a nucleic acid, e.g., mRNA, cDNA, DNA, encoding a CAR. In some such embodiments, the cell may transiently express the CAR.
  • a nucleic acid e.g., mRNA, cDNA, DNA
  • the CD33 binding domain, e.g., the human or humanized CD33 binding domain, of the CAR is a scFv antibody fragment.
  • such antibody fragments are functional in that they retain the equivalent binding affinity, e.g., they bind the same antigen with comparable efficacy, as the IgG antibody having the same heavy and light chain variable regions.
  • such antibody fragments are functional in that they provide a biological response that can include, but is not limited to, activation of an immune response, inhibition of signal-transduction origination from its target antigen, inhibition of kinase activity, and the like, as will be understood by a skilled artisan.
  • the antibodies of the invention are incorporated into a chimeric antigen receptor (CAR).
  • CAR comprises the polypeptide sequence provided herein as SEQ ID NOS: 48-56.
  • the CD33 binding domain e.g., humanized or human CD33 binding domain, portion of a CAR of the invention is encoded by a transgene whose sequence has been codon optimized for expression in a mammalian cell.
  • entire CAR construct of the invention is encoded by a transgene whose entire sequence has been codon optimized for expression in a mammalian cell. Codon optimization refers to the discovery that the frequency of occurrence of synonymous codons (i.e., codons that code for the same amino acid) in coding DNA is biased in different species. Such codon degeneracy allows an identical polypeptide to be encoded by a variety of nucleotide sequences.
  • a variety of codon optimization methods is known in the art, and include, e.g., methods disclosed in at least US Patent Numbers 5,786,464 and 6,114,148.
  • the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO:39-47. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 39. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 40. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 41. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 42. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 43. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 44.
  • the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 45. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 46. In one aspect, the human CD33 binding domain comprises the scFv portion provided in SEQ ID NO: 47.
  • the CARs of the invention combine an antigen binding domain of a specific antibody with an intracellular signaling molecule.
  • the intracellular signaling molecule includes, but is not limited to, CD3-zeta chain, 4- IBB and CD28 signaling modules and combinations thereof.
  • the antigen binding domain binds to CD33.
  • the CD33 CAR comprises a CAR selected from the sequence provided in one or more of SEQ ID NOS: 48-56. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 48. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 49. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 50. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 51. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 52. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 53. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 54. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 55. In one aspect, the CD33 CAR comprises the sequence provided in SEQ ID NO: 56.
  • the present invention provides CD33 CAR compositions and their use in medicaments or methods for treating, among other diseases, cancer or any malignancy or autoimmune diseases involving cells or tissues which express CD33.
  • the CAR of the invention can be used to eradicate CD33-expressing normal cells, thereby applicable for use as a cellular conditioning therapy prior to cell transplantation or other suitable therapy.
  • Cell transplantation includes stem cell transplantation, e.g., hematopoietic stem cell transplantation, and bone marrow transplantation.
  • the cell transplantation is allogeneic or autologous.
  • the CAR of the invention eradicates CD33-expressing normal cells or CD33-expressing cancer cells, or both, prior to cell transplantation or other suitable therapy.
  • the CD33-expressing normal cell is a CD33-expressing expressing myeloid progenitor cell and the cell transplantation is a stem cell transplantation.
  • the invention provides a cell (e.g., immune effector cell, e.g., T cell or NK cell) engineered to express a chimeric antigen receptor (e.g., immune effector cell, e.g., T cell or NK cell, e.g., CART) of the present invention, wherein the cell (e.g., immune effector cell, e.g., T cell or NK cell, e.g., "CART”) exhibits an antitumor property.
  • a cell e.g., immune effector cell, e.g., T cell or NK cell
  • a chimeric antigen receptor e.g., immune effector cell, e.g., T cell or NK cell, e.g., CART
  • the invention provides a CD33-CAR that comprises a CD33 binding domain and is engineered into a cell (e.g., an immune effector cell, e.g., T cell or NK cell) and methods of their use for adoptive therapy.
  • a cell e.g., an immune effector cell, e.g., T cell or NK cell
  • the antigen binding domain of the CAR comprises a human CD33 antibody or antibody fragment. In one aspect, the antigen binding domain of the CAR comprises a humanized CD33 antibody or antibody fragment. In one aspect, the antigen binding domain of the CAR comprises human CD33 antibody fragment comprising an scFv. In one aspect, the antigen binding domain of the CAR is a human CD33 scFv. In one aspect, the antigen binding domain of the CAR comprises a humanized CD33 antibody fragment comprising an scFv. In one aspect, the antigen binding domain of the CAR is a humanized CD33 scFv.
  • the CD33-CAR comprises at least one intracellular domain, e.g., described herein, e.g., selected from the group of a CD137 (4-1BB) signaling domain, a CD28 signaling domain, a CD3zeta signal domain, and any combination thereof.
  • the CD33-CAR comprises at least one intracellular signaling domain is from one or more co- stimulatory molecule(s) other than a CD 137 (4- IBB) or CD28.
  • the present invention also provides a CAR (e.g., a CAR polypeptide) that comprises an anti-CD33 binding domain (e.g., a CD33 binding domain as described herein), a transmembrane domain, and an intracellular signaling domain, and wherein said CD33 binding domain comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) of any heavy chain binding domain amino acid sequences listed in Table 2 or 9 .
  • HC CDR1 heavy chain complementary determining region 1
  • HC CDR2 heavy chain complementary determining region 2
  • HC CDR3 heavy chain complementary determining region 3
  • the CD33 binding domain of the CAR can further comprise a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) of any heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • LC CDR1 light chain complementary determining region 1
  • LC CDR2 light chain complementary determining region 2
  • LC CDR3 light chain complementary determining region 3
  • the present invention also provides nucleic acid molecules encoding the CAR as described herein, e.g., encoding a CAR that comprises a CD33 binding domain (e.g., as described herein), a transmembrane domain, and an intracellular signaling domain, and wherein said CD33 binding domain comprises a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) of any heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • HC CDR1 heavy chain complementary determining region 1
  • HC CDR2 heavy chain complementary determining region 2
  • HC CDR3 heavy chain complementary determining region 3
  • the encoded CD33 binding domain of the CAR can further comprise a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3) of any anti-BMCA heavy chain binding domain amino acid sequences listed in Table 2 or 9.
  • LC CDR1 light chain complementary determining region 1
  • LC CDR2 light chain complementary determining region 2
  • LC CDR3 light chain complementary determining region 3
  • a CAR construct of the invention comprises a human scFv domain selected from the group consisting of SEQ ID NOS:39-47, wherein the scFv may be preceded by an optional leader sequence such as provided in SEQ ID NO: 1, and followed by an optional hinge sequence such as provided in SEQ ID NO:2 or SEQ ID NO:3 or SEQ ID NO:4 or SEQ ID NO:5, a transmembrane region such as provided in SEQ ID NO:6, an intracellular signalling domain that includes SEQ ID NO:7 or SEQ ID NO: 8 and a CD3 zeta sequence that includes SEQ ID N0:9 or SEQ ID NO: 10, e.g., wherein the domains are contiguous with and in the same reading frame to form a single fusion protein.
  • nucleotide sequence that encodes the polypeptide of each of the human scFv fragments selected from the group consisting of SEQ ID NO:39-47. Also included in the invention is a nucleotide sequence that encodes the polypeptide of each of the human scFv fragments selected from the group consisting of SEQ ID NO: 39-47, and each of the domains of SEQ ID NOS: 1,2, and 6-9, plus the encoded CD33 CAR of the invention.
  • an exemplary CD33CAR construct comprises an optional leader sequence, an extracellular antigen binding domain, a hinge, a transmembrane domain, and an intracellular stimulatory domain. In one aspect, an exemplary CD33CAR construct comprises an optional leader sequence, an extracellular antigen binding domain, a hinge, a transmembrane domain, an intracellular costimulatory domain and an intracellular stimulatory domain.
  • CD33 CAR constructs containing humanized scFv domains of the invention are provided as SEQ ID NO: 138.
  • full-length CD33 CAR sequences are also provided herein as
  • An exemplary leader sequence is provided as SEQ ID NO: 1.
  • An exemplary hinge/spacer sequence is provided as SEQ ID NO:2 or SEQ ID NO:3 or SEQ ID NO:4 or SEQ ID NO:5.
  • An exemplary transmembrane domain sequence is provided as SEQ ID NO:6.
  • An exemplary sequence of the intracellular signaling domain of the 4-1BB protein is provided as SEQ ID NO: 7.
  • An exemplary sequence of the intracellular signaling domain of CD27 is provided as SEQ ID NO: 8.
  • An exemplary CD3zeta domain sequence is provided as SEQ ID NO: 9 or SEQ ID NO: 10.
  • the present invention encompasses a recombinant nucleic acid construct comprising a nucleic acid molecule encoding a CAR, wherein the nucleic acid molecule comprises the nucleic acid sequence encoding a CD33 binding domain, e.g., described herein, e.g., that is contiguous with and in the same reading frame as a nucleic acid sequence encoding an intracellular signaling domain.
  • a human CD33 binding domain is selected from one or more of SEQ ID NOS:39-47.
  • the human CD33 binding domain is SEQ ID NO: 39.
  • the human CD33 binding domain is SEQ ID NO: 40.
  • the human CD33 binding domain is SEQ ID NO: 41. In one aspect, the human CD33 binding domain is SEQ ID NO: 42. In one aspect, the human CD33 binding domain is SEQ ID NO: 43. In one aspect, the human CD33 binding domain is SEQ ID NO: 44. In one aspect, the human CD33 binding domain is SEQ ID NO: 45. In one aspect, the human CD33 binding domain is SEQ ID NO: 46. In one aspect, the human CD33 binding domain is SEQ ID NO: 47.
  • the present invention encompasses a recombinant nucleic acid construct comprising a nucleic acid molecule encoding a CAR, wherein the nucleic acid molecule comprises a nucleic acid sequence encoding a CD33 binding domain, e.g., wherein the sequence is contiguous with and in the same reading frame as the nucleic acid sequence encoding an intracellular signaling domain.
  • An exemplary intracellular signaling domain that can be used in the CAR includes, but is not limited to, one or more intracellular signaling domains of, e.g., CD3-zeta, CD28, 4-1BB, and the like. In some instances, the CAR can comprise any combination of CD3-zeta, CD28, 4- IBB, and the like.
  • the nucleic acid sequence of a CAR construct of the invention is selected from one or more of SEQ ID NOS:75-83.
  • the nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:75.
  • the nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:76.
  • the nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:77.
  • the nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:78.
  • the nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:79.
  • the nucleic acid sequence of a CAR construct comprises
  • nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:81. In one aspect, the nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:82. In one aspect, the nucleic acid sequence of a CAR construct comprises (e.g., consists of) SEQ ID NO:83.
  • nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques.
  • the nucleic acid of interest can be produced synthetically, rather than cloned.
  • the present invention includes retroviral and lentiviral vector constructs expressing a CAR that can be directly transduced into a cell.
  • the present invention also includes an RNA construct that can be directly transfected into a cell.
  • a method for generating mRNA for use in transfection involves in vitro transcription (IVT) of a template with specially designed primers, followed by polyA addition, to produce a construct containing 3' and 5' untranslated sequence ("UTR"), a 5' cap and/or Internal Ribosome Entry Site (IRES), the nucleic acid to be expressed, and a polyA tail, typically 50-2000 bases in length (SEQ ID NO:35).
  • RNA so produced can efficiently transfect different kinds of cells.
  • the template includes sequences for the CAR.
  • an RNA CAR vector is transduced into a cell by electroporation.
  • the CARs of the present invention comprise a target- specific binding element.
  • the choice of moiety depends upon the type and number of ligands that define the surface of a target cell.
  • the antigen binding domain may be chosen to recognize an antigen that acts as a cell surface marker on target cells associated with a particular disease state.
  • the CAR-mediated T-cell response can be directed to an antigen of interest by way of engineering an antigen binding domain that specifically binds a desired antigen into the CAR.
  • the CAR of the present invention comprises a binding domain that specifically binds to CD33. In one aspect, the CAR of the present invention comprises an antigen binding domain specifically binds to human CD33.
  • the antigen binding domain can be any protein that binds to the antigen including but not limited to a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, and a functional fragment thereof, including but not limited to a single-domain antibody such as a heavy chain variable domain (VH), a light chain variable domain (VL) and a variable domain (VHH) of camelid derived nanobody, and to an alternative scaffold known in the art to function as antigen binding domain, such as a recombinant fibronectin domain, and the like.
  • VH heavy chain variable domain
  • VL light chain variable domain
  • VHH variable domain
  • the antigen binding domain of the CAR may be beneficial for the antigen binding domain of the CAR to comprise human or humanized residues for the antigen binding domain of an antibody or antibody fragment.
  • the antigen binding domain comprises a human antibody or an antibody fragment.
  • the human CD33 binding domain comprises one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain
  • LC CDR2 complementary determining region 2
  • LC CDR3 light chain complementary determining region 3
  • HC CDR1 heavy chain complementary determining region 1
  • HC CDR2 heavy chain complementary determining region 2
  • HC CDR3 heavy chain complementary determining region 3
  • determining region 3 of a human CD33 binding domain described herein, e.g., a human CD33 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs.
  • the human CD33 binding domain comprises one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a human CD33 binding domain described herein, e.g., the human CD33 binding domain has two variable heavy chain regions, each comprising a HC CDR1, a HC CDR2 and a HC CDR3 described herein.
  • the human CD33 binding domain comprises a human light chain variable region described herein (e.g., in Table 4) and/or a human heavy chain variable region described herein (e.g., in Table 3).
  • the human CD33 binding domain comprises a human heavy chain variable region described herein (e.g., in Table 3), e.g., at least two human heavy chain variable regions described herein (e.g., in Table 3).
  • the CD33 binding domain is a scFv comprising a light chain and a heavy chain of an amino acid sequence of Tables 3-4.
  • the CD33 binding domain (e.g., an scFv) comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 4, or a sequence with 95-99% identity with an amino acid sequence of Table 5; and/or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 4, or a sequence with 95-99% identity to an amino acid sequence of Table 3.
  • a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g.
  • the human CD33 binding domain comprises a sequence selected from a group consisting of SEQ ID NO:39-47, or a sequence with 95-99% identity thereof.
  • the human CD33 binding domain is a scFv, and a light chain variable region comprising an amino acid sequence described herein, e.g., in Table 4, is attached to a heavy chain variable region comprising an amino acid sequence described herein, e.g., in Table 3, via a linker, e.g., a linker described herein.
  • the human CD33 binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 3 or 4 (SEQ ID NO:26).
  • the light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region.
  • the antigen binding domain comprises a humanized antibody or an antibody fragment.
  • the humanized CD33 binding domain comprises one or more (e.g., all three) light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2), and light chain complementary determining region 3 (LC CDR3) of a CD33 binding domain described herein, and/or one or more (e.g., all three) heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2), and heavy chain complementary determining region 3 (HC CDR3) of a CD33 binding domain described herein, e.g., a humanized CD33 binding domain comprising one or more, e.g., all three, LC CDRs and one or more, e.g., all three, HC CDRs.
  • the humanized CD33 binding domain includes a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 3 or 4 (SEQ ID NO:26).
  • the light chain variable region and heavy chain variable region of a scFv can be, e.g., in any of the following orientations: light chain variable region-linker-heavy chain variable region or heavy chain variable region-linker-light chain variable region.
  • the CD33 CAR that includes a humanized CD33 binding domain comprises SEQ ID NOS: 143.
  • a non-human antibody is humanized, where specific sequences or regions of the antibody are modified to increase similarity to an antibody naturally produced in a human or fragment thereof.
  • the antigen binding domain is humanized. Examples of humanized CD33 antibodies for use with CART described herein include hp67.6 or Gemtuzumab, as described in WO2012123755.
  • a humanized antibody can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated herein in its entirety by reference), veneering or resurfacing (see, e.g., European Patent Nos.
  • framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, which are incorporated herein by reference in their entireties.)
  • a humanized antibody or antibody fragment has one or more amino acid residues remaining in it from a source which is nonhuman. These nonhuman amino acid residues are often referred to as "import” residues, which are typically taken from an “import” variable domain.
  • humanized antibodies or antibody fragments comprise one or more CDRs from nonhuman immunoglobulin molecules and framework regions wherein the amino acid residues comprising the framework are derived completely or mostly from human germline.
  • Humanized antibodies are often human antibodies in which some CDR residues and possibly some framework (FR) residues are substituted by residues from analogous sites in rodent antibodies.
  • Humanization of antibodies and antibody fragments can also be achieved by veneering or resurfacing (EP 592,106; EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., Protein Engineering, 7(6):805-814 (1994); and Roguska et al., PNAS, 91:969-973 (1994)) or chain shuffling (U.S. Pat. No. 5,565,332), the contents of which are incorporated herein by reference herein in their entirety.
  • variable domains both light and heavy
  • the choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is to reduce antigenicity.
  • sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences.
  • the human sequence which is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody (Sims et al., J. Immunol., 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987), the contents of which are incorporated herein by reference herein in their entirety).
  • Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains.
  • the same framework may be used for several different humanized antibodies (see, e.g., Nicholson et al. Mol. Immun. 34 (16-17): 1157-1165 (1997); Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol., 151:2623 (1993), the contents of which are incorporated herein by reference herein in their entirety).
  • the framework region e.g., all four framework regions, of the heavy chain variable region are derived from a VH4_4-59 germline sequence.
  • the framework region can comprise, one, two, three, four or five modifications, e.g., substitutions, e.g., from the amino acid at the corresponding murine sequence (e.g., of SEQ ID NO: 138).
  • the framework region e.g., all four framework regions of the light chain variable region are derived from a VK3_1.25 germline sequence.
  • the framework region can comprise, one, two, three, four or five modifications, e.g., substitutions, e.g., from the amino acid at the corresponding murine sequence (e.g., of SEQ ID NO: 138).
  • the portion of a CAR composition of the invention that comprises an antibody fragment is humanized with retention of high affinity for the target antigen and other favorable biological properties.
  • humanized antibodies and antibody fragments are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, e.g., the analysis of residues that influence the ability of the candidate immunoglobulin to bind the target antigen.
  • FR residues can be selected and combined from the recipient and import sequences so that the desired antibody or antibody fragment characteristic, such as increased affinity for the target antigen, is achieved.
  • the CDR residues are directly and most substantially involved in influencing antigen binding.
  • a humanized antibody or antibody fragment may retain a similar antigenic specificity as the original antibody, e.g., in the present invention, the ability to bind human CD33 or a fragment thereof.
  • a humanized antibody or antibody fragment may have improved affinity and/or specificity of binding to human CD33or a fragment thereof.
  • the antigen binding domain portion comprises one or more sequence selected from SEQ ID NOs:39-47.
  • the CD33 CARthat includes a human CD33 binding domain is selected from one or more sequence selected from SEQ ID NOs: 48-56.
  • the CD33 binding domain is characterized by particular functional features or properties of an antibody or antibody fragment.
  • the portion of a CAR composition of the invention that comprises an antigen binding domain specifically binds human CD33 or a fragment thereof.
  • the invention relates to an antigen binding domain comprising an antibody or antibody fragment, wherein the antibody binding domain specifically binds to a CD33 protein or fragment thereof, wherein the antibody or antibody fragment comprises a variable light chain and/or a variable heavy chain that includes an amino acid sequence of SEQ ID NO: 48-56.
  • the antigen binding domain comprises an amino acid sequence of an scFv selected from SEQ ID NO: 39-47.
  • the scFv is contiguous with and in the same reading frame as a leader sequence.
  • the leader sequence is the polypeptide sequence provided as SEQ ID NO:l.
  • the CD33 binding domain is a fragment, e.g., a single chain variable fragment (scFv).
  • the CD33 binding domain is a Fv, a Fab, a (Fab')2, or a bi- functional (e.g. bi-specific) hybrid antibody (e.g., Lanzavecchia et al., Eur. J. Immunol. 17, 105 (1987)).
  • the antibodies and fragments thereof of the invention binds a CD33 protein or a fragment thereof with wild-type or enhanced affinity.
  • a human scFv can be derived from a display library.
  • a display library is a collection of entities; each entity includes an accessible polypeptide component and a recoverable component that encodes or identifies the polypeptide component.
  • the polypeptide component is varied so that different amino acid sequences are represented.
  • the polypeptide component can be of any length, e.g. from three amino acids to over 300 amino acids.
  • a display library entity can include more than one polypeptide component, for example, the two polypeptide chains of a Fab.
  • a display library can be used to identify a human CD33 binding domain. In a selection, the polypeptide component of each member of the library is probed with CD33, or a fragment thereof, and if the polypeptide component binds to CD33, the display library member is identified, typically by retention on a support.
  • Retained display library members are recovered from the support and analyzed.
  • the analysis can include amplification and a subsequent selection under similar or dissimilar conditions. For example, positive and negative selections can be alternated.
  • the analysis can also include determining the amino acid sequence of the polypeptide component, i.e., the anti- CD33 binding domain, and purification of the polypeptide component for detailed
  • a variety of formats can be used for display libraries. Examples include the phaage display.
  • the protein component is typically covalently linked to a bacteriophage coat protein.
  • the linkage results from translation of a nucleic acid encoding the protein component fused to the coat protein.
  • the linkage can include a flexible peptide linker, a protease site, or an amino acid incorporated as a result of suppression of a stop codon.
  • Phage display is described, for example, in U.S.
  • Bacteriophage displaying the protein component can be grown and harvested using standard phage preparatory methods, e.g. PEG precipitation from growth media. After selection of individual display phages, the nucleic acid encoding the selected protein components can be isolated from cells infected with the selected phages or from the phage themselves, after amplification. Individual colonies or plaques can be picked, the nucleic acid isolated and sequenced.
  • display formats include cell based display (see, e.g., WO 03/029456), protein- nucleic acid fusions (see, e.g., US 6,207,446), ribosome display (See, e.g., Mattheakis et al. (1994) Proc. Natl. Acad. Sci. USA 91:9022 and Hanes et al. (2000) Nat Biotechnol. 18:1287- 92; Hanes et al. (2000) Methods Enzymol. 328:404-30; and Schaffitzel et al. (1999) J Immunol Methods. 231(l-2):119-35), and E. coli periplasmic display (2005 Nov 22;PMID: 16337958).
  • scFvs can be prepared according to method known in the art (see, for example, Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • ScFv molecules can be produced by linking VH and VL regions together using flexible polypeptide linkers.
  • the scFv molecules comprise a linker (e.g., a Ser-Gly linker) with an optimized length and/or amino acid composition. The linker length can greatly affect how the variable regions of a scFv fold and interact.
  • a short polypeptide linker e.g., between 5-10 amino acids
  • intrachain folding is prevented.
  • Interchain folding is also required to bring the two variable regions together to form a functional epitope binding site.
  • linker orientation and size see, e.g., Hollinger et al. 1993 Proc Natl Acad. Sci. U.S.A. 90:6444-6448, U.S. Patent Application Publication Nos. 2005/0100543, 2005/0175606, 2007/0014794, and PCT publication Nos.
  • An scFv can comprise a linker of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more amino acid residues between its VL and VH regions.
  • the linker sequence may comprise any naturally occurring amino acid.
  • the linker sequence comprises amino acids glycine and serine.
  • the linker sequence comprises sets of glycine and serine repeats such as
  • the linker can be (Gly 4 Ser) 4 (SEQ ID NO:27) or (Gly 4 Ser) 3 (SEQ ID NO:28). Variation in the linker length may retain or enhance activity, giving rise to superior efficacy in activity studies.
  • Exemplary CD33 CAR constructs disclose herein comprise an scFv (e.g., a human scFv as disclosed in Tables 2 and 9 herein, optionally preceded with an optional leader sequence (e.g., SEQ ID NO:l and SEQ ID NO: 12 for exemplary leader amino acid and nucleotide sequences, respectively).
  • the sequences of the human scFv fragments (SEQ ID NOs: 39-83, including the optional leader sequence) are provided herein in Table 2.
  • the sequences of human scFv fragments, without the leader sequence are provided herein in Table 9 (SEQ ID NOS: 255-261 for the nucleotide sequences, and SEQ ID NOs: 262-268 for the amino acid sequences).
  • the CD33 CAR construct can further include an optional hinge domain, e.g., a CD8 hinge domain (e.g., including the amino acid sequence of SEQ ID NO: 2 or encoded by a nucleic acid sequence of SEQ ID NO: 13); a transmembrane domain, e.g., a CD8
  • transmembrane domain e.g., including the amino acid sequence of SEQ ID NO: 6 or encoded by the nucleotide sequence of SEQ ID NO: 17
  • an intracellular domain e.g., a 4- IBB intracellular domain (e.g., including the amino acid sequence of SEQ ID NO: 7 or encoded by the nucleotide sequence of SEQ ID NO: 18
  • a functional signaling domain e.g., a CD3 zeta domain (e.g., including amino acid sequence of SEQ ID NO: 9 or 10, or encoded by the nucleotide sequence of SEQ ID NO: 20 or 21).
  • the domains are contiguous with and in the same reading frame to form a single fusion protein.
  • the domain are in separate polypeptides, e.g., as in an RCAR molecule as described herein.
  • the full length CD33 CAR molecule includes the amino acid sequence of, or is encoded by the nucleotide sequence of, CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 2, or a sequence substantially (e.g., 95-99%) identical thereto.
  • the CD33 CAR molecule, or the anti-CD33 antigen binding domain includes the scFv amino acid sequence of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 2 (with or without the leader sequence); or includes the scFv amino acid sequence of, or is encoded by the nucleotide sequence of, CAR33-1, CAR33-2, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-9, provided in Table 9, or a sequence substantially identical (e.g., 95-99% identical, or up to 20, 15, 10, 8, 6, 5, 4, 3, 2, or 1 amino acid changes, e.g., substitutions (e.g., conservative substitutions)) to any of the aforesaid sequences.
  • substitutions e.g., conservative substitutions
  • the CD33 CAR molecule, or the anti-CD33 antigen binding domain includes the heavy chain variable region and/or the light chain variable region of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 2, or a sequence substantially identical (e.g., 95-99% identical, or up to 20, 15, 10, 8, 6, 5, 4, 3, 2, or 1 amino acid changes, e.g., substitutions (e.g., conservative substitutions)) to any of the aforesaid sequences.
  • substitutions e.g., conservative substitutions
  • the CD33 CAR molecule, or the anti-CD33 antigen binding domain includes one, two or three CDRs from the heavy chain variable region (e.g., HC CDRl, HC CDR2 and/or HC CDR3), provided in Table 3; and/or one, two or three CDRs from the light chain variable region (e.g., LC CDRl, LC CDR2 and/or LC CDR3) of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 4; or a sequence substantially identical (e.g., 95-99% identical, or up to 5, 4, 3, 2, or 1 amino acid changes, e.g., substitutions (e.g., conservative substitutions)) to any of the aforesaid sequences.
  • the heavy chain variable region e.g., HC CDRl, HC CDR2 and/or HC CDR3
  • the CD33 CAR molecule, or the anti-CD33 antigen binding domain includes one, two or three CDRs from the heavy chain variable region (e.g., HC CDRl, HC CDR2 and/or HC CDR3), provided in Table 10; and/or one, two or three CDRs from the light chain variable region (e.g., LC CDRl, LC CDR2 and/or LC CDR3) of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 11; or a sequence substantially identical (e.g., 95-99% identical, or up to 5, 4, 3, 2, or 1 amino acid changes, e.g., substitutions (e.g., conservative substitutions)) to any of the aforesaid sequences.
  • the heavy chain variable region e.g., HC CDRl, HC CDR2 and/or HC CDR3
  • the CD33 CAR molecule, or the anti-CD33 antigen binding domain includes one, two or three CDRs from the heavy chain variable region (e.g., HC CDR1, HC CDR2 and/or HC CDR3), provided in Table 12; and/or one, two or three CDRs from the light chain variable region (e.g., LCDR1, LCDR2 and/or LCDR3) of CAR33-1, CAR33-2, CAR33-3, CAR33-4, CAR33-5, CAR33-6, CAR33-7, CAR33-8, CAR33-9, provided in Table 13; or a sequence substantially identical (e.g., 95-99% identical, or up to 5, 4, 3, 2, or 1 amino acid changes, e.g., substitutions (e.g., conservative substitutions)) to any of the aforesaid sequences.
  • the heavy chain variable region e.g., HC CDR1, HC CDR2 and/or HC CDR3
  • the light chain variable region e.g.
  • the sequences of human CDR sequences of the scFv domains are shown in Table 3 for the heavy chain variable domains and in Table 4 for the light chain variable domains.
  • ID stands for the respective SEQ ID NO for each CDR.
  • the CDRs provided in Tables 3 and 4 are according to a combination of the Kabat and Chothia numbering scheme.
  • the CAR molecule described herein e.g., the CAR nucleic acid or the CAR polypeptide
  • a CD33 binding domain includes:
  • LC CDRs chosen from one of the following:
  • the CAR molecule described herein (e.g., the CAR nucleic acid or the CAR polypeptide) includes:
  • LC CDRs chosen from one of the following:
  • HC CDRs chosen from one of the following:
  • the CAR molecule described herein (e.g., the CAR nucleic acid or the CAR polypeptide) includes:
  • LC CDRs chosen from one of the following:
  • HC CDRs chosen from one of the following:
  • fully human anti-CD33 single chain variable fragments are generated and cloned into a lentiviral expression vector with the intracellular CD3zeta chain and the intracellular co-stimulatory domain of 4-lBB.
  • Names of exemplary fully human anti- CD33 scFvs are depicted in Table 1.
  • the order in which the VL and VH domains appear in the scFv is varied (i.e., VL-VH, or VH-VL orientation), and where either three or four copies of the "G4S" (SEQ ID NO:25) subunit, in which each subunit comprises the sequence GGGGS (SEQ ID NO:25) (e.g., (G4S) 3 (SEQ ID NO:28) or (G4S) 4 (SEQ ID NO:27)), connect the variable domains to create the entirety of the scFv domain, as shown in Table 3.
  • Exemplary sequences of the human scFv fragments are provided herein in Table 2. It is noted that the scFv fragments of SEQ ID NOs: 39-83, without a leader sequence (e.g., without the amino acid sequence of SEQ ID NO: 1 or the nucleotide sequence of SEQ ID NO: 12), are also encompassed by the present invention. Exemplary sequences of human scFv fragments, without the leader sequence, are provided herein in Table 9 (SEQ ID NOS: 255-261 for the nucleotide sequences, and SEQ ID NOS: 262-268 for the amino acid sequences). Leader (amino acid sequence) (SEQ ID NO: 1)
  • MALPVTALLLPLALLLHAARP leader (nucleic acid sequence) (SEQ ID NO: 12)
  • CD8 hinge amino acid sequence (SEQ ID NO: 2)
  • CD8 hinge (nucleic acid sequence) (SEQ ID NO: 13)
  • CD8 transmembrane (amino acid sequence) (SEQ ID NO: 6)
  • CD8 transmembrane (nucleic acid sequence) (SEQ ID NO: 17)
  • CD28 Intracellular domain (amino acid sequence) (SEQ ID NO: 379)
  • RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO: 379) CD28 Intracellular domain (nucleotide sequence) (SEQ ID NO: 380)
  • ICOS Intracellular domain (amino acid sequence) (SEQ ID NO: 381)
  • ICOS Intracellular domain (nucleotide sequence) (SEQ ID NO: 382)
  • CD3 zeta domain (amino acid sequence) (SEQ ID NO: 9)
  • IgG4 Hinge (nucleotide sequence) (SEQ ID NO:37)
  • GQGLEWMGWINPNSGVTKYAQKFQGRVTMTRNTS I STAYMELSSLRSEDTAVYYCATWYS SG CAR33-8
  • GQGLEWMGWINPNSGVTKYAQKFQGRVTMTRNTS I STAYMELSSLRSEDTAVYYCATWYS SG CAR33-8
  • KFQGRVTMTRNTS I STAYMELS SLRSEDTAVYYCATWYSSGWYGIANIWGQGTMVTVS S
  • CAR scFv fragments are cloned into lentiviral vectors to create a full length CAR construct in a single coding frame, and using a promoter, e.g., EFl alpha promoter, for expression (SEQ ID NO: 11).
  • a promoter e.g., EFl alpha promoter
  • This sequence may encompass 1-6 "Gly Gly Gly Gly Ser" repeating units
  • GGGS PolyA (A) 500 o (SEQ ID NO:30)
  • PolyA (T) 100 (SEQ ID NO:31)
  • PolyA (A) 500 o (SEQ ID NO:33)
  • This sequence may encompass 100-5000 adenines.
  • PolyA (A) 400 (SEQ ID NO:34) PolyA: (A) 200 o (SEQ ID NO:35)
  • Gly/Ser SEQ ID NO:38: This sequence may encompass 1-10 "Gly Gly Gly Ser” repeating units
  • Example 3 provides the following: the nucleotide sequence of 2213 murine anti- CD33 IgG4 nucleotide sequence (SEQ ID NO: 138); the 2213 CAR nucleotide sequence (SEQ ID NO: 139); the 2213 CAR amino acid sequence (SEQ ID NO: 140); the 2213 scFv nucleotide sequence (SEQ ID NO: 141); and the 2213 scFv amino acid sequence (SEQ ID NO: 142); the 2218 humanized anti-CD33 IgG4H nucleotide sequence (SEQ ID NO: 143).
  • Example 3 Other embodiments disclosed in Example 3 include CAR molecules and anti-CD33 antibody fragments of Gemtuzumab ozogamicin previously marketed as Mylotarg) (e.g., the humanized version described herein as "humanized my96").
  • the amino acid sequence of anti- CD33 scFv of Gemtuzumab ozogamicin (an immunoconjugate targeting CD33) with 41BB and CD3 zeta signaling domains is described in Example 3; and SEQ ID NO: 145.
  • nucleotide sequence of humanized my96 is depicted as SEQ ID NO: 144.
  • the humanized my96 nucleotide sequence is provided herein as SEQ ID NO: 146, and the amino acid sequence is SEQ ID NO: 147.
  • the CD33 CAR and CD33 CART decribed herein comprise an antigen binding domain comprising one or more, e.g., one, two, or three, CDRs of the heavy chain variable domain and/or one or more, e.g., one, two, or three, CDRs of the light chain variable domain, or the VH or VL of the scFv sequence encoded by GenBank reference no. AM402974.1 (See, Wang et al., Mol. Ther., vol. 23:1, pp. 184-191 (2015), hereby incorporated by reference.
  • the CAR scFv fragments can be cloned into lentiviral vectors to create a full length CAR construct in a single coding frame, and using the EFl alpha promoter for expression (SEQ ID NO: 11).
  • the CAR construct can include a Gly/Ser linker having one or more of the following sequences: GGGGS (SEQ ID NO:25); encompassing 1-6 "Gly Gly Gly Gly Ser" repeating units, e.g., GGGGSGGGGS GGGGSGGGGS GGGGSGGGGS (SEQ ID NO:26);
  • GGGGSGGGGS GGGGSGGGGS SEQ ID NO:27
  • GGGGSGGGGS GGGGS SEQ ID NO:28
  • GGGS SEQ ID NO:29
  • Gly Gly Gly Ser repeating units, e.g., GGGSGGGSGG GSGGGSGGGSGGGSGG GSGGGSGGGS (SEQ ID NO:38).
  • the CAR construct include a poly A sequence, e.g., a sequence encompassing 50-5000 or 100-5000 adenines (e.g., SEQ ID NO:30, SEQ ID NO:33, SEQ ID NO:34 or SEQ ID NO:35), or a sequence encompassing 50-5000 thymines (e.g., SEQ ID NO:31, SEQ ID NO:32).
  • the CAR construct can include, for example, a linker including the sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO: 383)
  • a multispecific antibody molecule is a bispecific antibody molecule.
  • a bispecific antibody has specificity for no more than two antigens.
  • a bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence which has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope.
  • the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein).
  • the first and second epitopes overlap.
  • the first and second epitopes do not overlap.
  • first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein).
  • a bispecific antibody molecule comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope.
  • a bispecific antibody molecule comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope.
  • a bispecific antibody molecule comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope.
  • a bispecific antibody molecule comprises a scFv, or fragment thereof, have binding specificity for a first epitope and a scFv, or fragment thereof, have binding specificity for a second epitope.
  • the antibody molecule is a multi- specific (e.g., a bispecific or a trispecific) antibody molecule.
  • Protocols for generating bispecific or heterodimeric antibody molecules are known in the art; including but not limited to, for example, the "knob in a hole" approach described in, e.g., US 5731168; the electrostatic steering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905 and WO 2010/129304; Strand Exchange Engineered Domains (SEED) heterodimer formation as described in, e.g., WO 07/110205; Fab arm exchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO 2013/060867; double antibody conjugate, e.g., by antibody cross-linking to generate a bi-specific structure using a heterobifunctional reagent having an amine-reactive group and a sulfhydryl reactive group as described
  • the VH can be upstream or downstream of the VL.
  • the upstream antibody or antibody fragment e.g., scFv
  • the downstream antibody or antibody fragment is arranged with its VL (VL 2 ) upstream of its VH (VH 2 ), such that the overall bispecific antibody molecule has the arrangement VHi-VLi-VL 2 -VH 2 .
  • the upstream antibody or antibody fragment (e.g., scFv) is arranged with its VL (VLi) upstream of its VH (VHi) and the downstream antibody or antibody fragment (e.g., scFv) is arranged with its VH (VH 2 ) upstream of its VL (VL 2 ), such that the overall bispecific antibody molecule has the arrangement VLi- VHi-VH 2 -VL 2 .
  • a linker is disposed between the two antibodies or antibody fragments (e.g., scFvs), e.g., between VLi and VL 2 if the construct is arranged as VH VLi- VL 2 -VH 2 , or between VHi and VH 2 if the construct is arranged as VLi-VH VH 2 -VL 2 .
  • the linker may be a linker as described herein, e.g., a (Gly 4 -Ser)n linker, wherein n is 1, 2, 3, 4, 5, or 6, preferably 4 (SEQ ID NO: 26).
  • the linker between the two scFvs should be long enough to avoid mispairing between the domains of the two scFvs.
  • a linker is disposed between the VL and VH of the first scFv.
  • a linker is disposed between the VL and VH of the second scFv.
  • any two or more of the linkers can be the same or different.
  • a bispecific CAR comprises VLs, VHs, and optionally one or more linkers in an arrangement as described herein.
  • the bispecific antibody molecule is characterized by a first immunoglobulin variable domain sequence, e.g., a scFv, which has binding specificity for CD33, e.g., comprises a scFv as described herein, e.g., as described in Table 2 or Table 9, or comprises the light chain CDRs and/or heavy chain CDRs from a CD33 scFv described herein, and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope on a different antigen.
  • the second immunoglobulin variable domain sequence has binding specificity for an antigen expressed on AML cells, e.g., an antigen other than CD33.
  • the second immunoglobulin variable domain sequence has binding specificity for CD 123.
  • the second immunoglobulin variable domain sequence has binding specificity for CLL-1.
  • the second immunoglobulin variable domain sequence has binding specificity for CD34.
  • the second immunoglobulin variable domain sequence has binding specificity for FLT3.
  • the second immunoglobulin variable domain sequence has binding specificity for folate receptor beta.
  • the second immunoglobulin variable domain sequence has binding specificity for an antigen expressed on B-cells, for example, CD19, CD20, CD22 or ROR1.
  • the CD33 antibodies and antibody fragments of the present invention can be grafted to one or more constant domain of a T cell receptor (“TCR") chain, for example, a TCR alpha or TCR beta chain, to create an chimeric TCR that binds specificity to CD33.
  • TCR T cell receptor
  • chimeric TCRs will signal through the TCR complex upon antigen binding.
  • a CD33 scFv as disclosed herein can be grafted to the constant domain, e.g., at least a portion of the extracellular constant domain, the transmembrane domain and the cytoplasmic domain, of a TCR chain, for example, the TCR alpha chain and/or the TCR beta chain.
  • a CD33 antibody fragment for example a VL domain as described herein, can be grafted to the constant domain of a TCR alpha chain
  • a CD33 antibody fragment for example a VH domain as described herein, can be grafted to the constant domain of a TCR beta chain (or alternatively, a VL domain may be grafted to the constant domain of the TCR beta chain and a VH domain may be grafted to a TCR alpha chain).
  • the CDRs of a CD33 antibody or antibody fragment may be grafted into a TCR alpha and/or beta chain to create a chimeric TCR that binds specifically to CD33.
  • the LCDRs disclosed herein may be grafted into the variable domain of a TCR alpha chain and the HCDRs disclosed herein may be grafted to the variable domain of a TCR beta chain, or vice versa.
  • Such chimeric TCRs may be produced by methods known in the art (For example, Willemsen RA et al, Gene Therapy 2000; 7: 1369-1377; Zhang T et al, Cancer Gene Ther 2004; 11: 487- 496; Aggen et al, Gene Ther. 2012 Apr;19(4):365-74).
  • a CAR can be designed to comprise a transmembrane domain that is attached to the extracellular domain of the CAR.
  • a transmembrane domain can include one or more additional amino acids adjacent to the transmembrane region, e.g., one or more amino acid associated with the extracellular region of the protein from which the transmembrane was derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the extracellular region) and/or one or more additional amino acids associated with the intracellular region of the protein from which the transmembrane protein is derived (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 up to 15 amino acids of the intracellular region).
  • the transmembrane domain is one that is associated with one of the otherdomains of the CAR is used.
  • the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins, e.g., to minimize interactions with other members of the receptor complex.
  • the transmembrane domain is capable of
  • the amino acid sequence of the transmembrane domain may be modified or substituted so as to minimize interactions with the binding domains of the native binding partner present in the same CAR-expressing cell, e.g., CART.
  • the transmembrane domain may be derived either from a natural or from a recombinant source. Where the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In one aspect the transmembrane domain is capable of signaling to the intracellular domain(s) whenever the CAR has bound to a target.
  • a transmembrane domain of particular use in this invention may include at least the transmembrane region(s) of e.g., the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD 8 (e.g., CD8 alpha, CD 8 beta), CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154.
  • a transmembrane domain may include at least the transmembrane region(s) of, e.g., KIRDS2, OX40, CD2, CD27, LFA-1 (CDl la, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD160, CD19, IL2R beta, IL2R gamma, IL7R a, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA- 6, CD49f, ITGAD, CDl ld, ITGAE, CD103, ITGAL, CDl la, LFA-1, ITGAM, CDl lb, ITGAX, CDl lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2,
  • the transmembrane domain can be attached to the extracellular region of the CAR, e.g., the antigen binding domain of the CAR, via a hinge, e.g., a hinge from a human protein.
  • a hinge e.g., a hinge from a human protein.
  • the hinge can be a human Ig
  • the hinge or spacer comprises (e.g., consists of) the amino acid sequence of SEQ ID NO:2.
  • the transmembrane domain comprises (e.g., consists of) a transmembrane domain of SEQ ID NO: 6.
  • the hinge or spacer comprises an IgG4 hinge.
  • the hinge or spacer comprises a hinge of the amino acid sequence
  • the hinge or spacer comprises a hinge encoded by a nucleotide sequence of
  • the hinge or spacer comprises a hinge encoded by a nucleotide sequence of
  • the transmembrane domain may be recombinant, in which case it will comprise predominantly hydrophobic residues such as leucine and valine.
  • a triplet of phenylalanine, tryptophan and valine can be found at each end of a recombinant
  • a short oligo- or polypeptide linker may form the linkage between the transmembrane domain and the cytoplasmic region of the CAR.
  • a glycine-serine doublet provides a particularly suitable linker.
  • the linker comprises the amino acid sequence of GGGGSGGGGS (SEQ ID NO:5).
  • the linker is encoded by a nucleotide sequence of
  • the hinge or spacer comprises a KIR2DS2 hinge.
  • the cytoplasmic domain or region of the present CAR includes an intracellular signaling domain.
  • An intracellular signaling domain is capable of activation of at least one of the normal effector functions of the immune cell in which the CAR has been introduced.
  • Examples of intracellular signaling domains for use in the CAR of the invention include the cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen receptor engagement, as well as any derivative or variant of these sequences and any recombinant sequence that has the same functional capability. It is known that signals generated through the TCR alone are insufficient for full activation of the T cell and that a secondary and/or costimulatory signal is also required.
  • T cell activation can be said to be mediated by two distinct classes of cytoplasmic signaling sequences: those that initiate antigen-dependent primary activation through the TCR (primary intracellular signaling domains) and those that act in an antigen-independent manner to provide a secondary or costimulatory signal (secondary cytoplasmic domain, e.g., a costimulatory domain).
  • a primary signaling domain regulates primary activation of the TCR complex either in a stimulatory way, or in an inhibitory way.
  • Primary intracellular signaling domains that act in a stimulatory manner may contain signaling motifs which are known as immunoreceptor tyrosine-based activation motifs or ITAMs.
  • IT AM containing primary intracellular signaling domains examples include those of TCR zeta, FcR gamma, FcR beta, CD3 gamma, CD3 delta , CD3 epsilon, CD5, CD22, CD79a, CD79b, CD278 (also known as "ICOS"), FcsRI, DAP10, DAP12, and CD66d.
  • a CAR of the invention comprises an intracellular signaling domain, e.g., a primary signaling domain of CD3-zeta.
  • a primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain which has altered (e.g., increased or decreased) activity as compared to the native ⁇ domain.
  • a primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain, e.g., an optimized and/or truncated ITAM-containing primary intracellular signaling domain.
  • a primary signaling domain comprises one, two, three, four or more ITAM motifs.
  • molecules containing a primary intracellular signaling domain that are of particular use in the invention include those of DAP10, DAP12, and CD32.
  • the intracellular signalling domain of the CAR can comprise the primary signalling domain, e.g., CD3-zeta signaling domain, by itself or it can be combined with any other desired intracellular signaling domain(s) useful in the context of a CAR of the invention.
  • the intracellular signaling domain of the CAR can comprise a primary signalling domain, e.g., CD3 zeta chain portion, and a costimulatory signaling domain.
  • the costimulatory signaling domain refers to a portion of the CAR comprising the intracellular domain of a costimulatory molecule.
  • a costimulatory molecule is a cell surface molecule other than an antigen receptor or its ligands that is required for an efficient response of lymphocytes to an antigen.
  • MHC class I molecule examples include MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, OX40, CD2, CD7, CD27, CD28, CD30, CD40, CDS, ICAM-1, LFA-1 (CDl la/CD18), 4-1BB (CD137), B7-H3, CDS, ICAM-1, ICOS (CD278), GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2,
  • TRANCE/RANKL DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMFl, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, and a ligand that specifically binds with CD83, and the like.
  • the intracellular signaling sequences within the cytoplasmic portion of the CAR of the invention may be linked to each other in a random or specified order.
  • a short oligo- or polypeptide linker for example, between 2 and 10 amino acids (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) in length may form the linkage between intracellular signaling sequence.
  • a glycine- serine doublet can be used as a suitable linker.
  • a single amino acid e.g., an alanine, a glycine
  • a suitable linker e.g., an alanine, a glycine

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Cell Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Virology (AREA)
  • Diabetes (AREA)
  • Peptides Or Proteins (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
PCT/US2015/041390 2014-07-21 2015-07-21 Treatment of cancer using a cd33 chimeric antigen receptor Ceased WO2016014576A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
AU2015292755A AU2015292755B2 (en) 2014-07-21 2015-07-21 Treatment of cancer using a CD33 chimeric antigen receptor
JP2017503497A JP6831777B2 (ja) 2014-07-21 2015-07-21 Ｃｄ３３キメラ抗原受容体を使用する癌の処置
MX2017001008A MX390943B (es) 2014-07-21 2015-07-21 Receptores de antígeno quimérico cd33 y usos de los mismos.
EP15745069.3A EP3172234B1 (en) 2014-07-21 2015-07-21 Treatment of cancer using a cd33 chimeric antigen receptor
KR1020177004379A KR102594343B1 (ko) 2014-07-21 2015-07-21 Cd33 키메라 항원 수용체를 사용한 암의 치료
ES15745069T ES2805475T3 (es) 2014-07-21 2015-07-21 Tratamiento del cáncer utilizando un receptor antigénico quimérico de CD33
BR112017001242A BR112017001242A2 (pt) 2014-07-21 2015-07-21 tratamento de câncer usando um receptor antigênico quimérico a cd33
EP20160131.7A EP3722316A1 (en) 2014-07-21 2015-07-21 Treatment of cancer using a cd33 chimeric antigen receptor
RU2017105160A RU2747384C2 (ru) 2014-07-21 2015-07-21 Лечение рака с помощью химерного антигенного рецептора к cd33
SG11201700416TA SG11201700416TA (en) 2014-07-21 2015-07-21 Treatment of cancer using a cd33 chimeric antigen receptor
CA2955154A CA2955154C (en) 2014-07-21 2015-07-21 Treatment of cancer using a cd33 chimeric antigen receptor
CN201580050572.3A CN107109419B (zh) 2014-07-21 2015-07-21 使用cd33嵌合抗原受体治疗癌症
ZA2017/00157A ZA201700157B (en) 2014-07-21 2017-01-09 Treatment of cancer using a cd33 chimeric antigen receptor
IL250138A IL250138B (en) 2014-07-21 2017-01-16 Cancer treatment using chimeric cd33 receptor antigen
CONC2017/0000510A CO2017000510A2 (es) 2014-07-21 2017-01-20 Constructos de car
AU2021200929A AU2021200929A1 (en) 2014-07-21 2021-02-12 Treatment of cancer using a CD33 chimeric antigen receptor

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CNPCT/CN2014/082589 2014-07-21
CN2014082589 2014-07-21
CN2014090504 2014-11-06
CNPCT/CN2014/090504 2014-11-06

Publications (1)

Publication Number Publication Date
WO2016014576A1 true WO2016014576A1 (en) 2016-01-28

Family

ID=53765585

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/041390 Ceased WO2016014576A1 (en) 2014-07-21 2015-07-21 Treatment of cancer using a cd33 chimeric antigen receptor

Country Status (17)

Country Link
US (4) US9777061B2 (cg-RX-API-DMAC7.html)
EP (2) EP3722316A1 (cg-RX-API-DMAC7.html)
JP (2) JP6831777B2 (cg-RX-API-DMAC7.html)
KR (1) KR102594343B1 (cg-RX-API-DMAC7.html)
CN (2) CN112481283A (cg-RX-API-DMAC7.html)
AU (2) AU2015292755B2 (cg-RX-API-DMAC7.html)
BR (1) BR112017001242A2 (cg-RX-API-DMAC7.html)
CA (1) CA2955154C (cg-RX-API-DMAC7.html)
CO (1) CO2017000510A2 (cg-RX-API-DMAC7.html)
ES (1) ES2805475T3 (cg-RX-API-DMAC7.html)
IL (1) IL250138B (cg-RX-API-DMAC7.html)
MX (1) MX390943B (cg-RX-API-DMAC7.html)
RU (1) RU2747384C2 (cg-RX-API-DMAC7.html)
SG (2) SG11201700416TA (cg-RX-API-DMAC7.html)
TW (1) TWI719942B (cg-RX-API-DMAC7.html)
WO (1) WO2016014576A1 (cg-RX-API-DMAC7.html)
ZA (1) ZA201700157B (cg-RX-API-DMAC7.html)

Cited By (134)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015427A1 (en) 2015-07-21 2017-01-26 Novartis Ag Methods for improving the efficacy and expansion of immune cells
WO2017040930A2 (en) 2015-09-03 2017-03-09 The Trustees Of The University Of Pennsylvania Biomarkers predictive of cytokine release syndrome
WO2017114497A1 (en) 2015-12-30 2017-07-06 Novartis Ag Immune effector cell therapies with enhanced efficacy
US9745368B2 (en) 2013-03-15 2017-08-29 The Trustees Of The University Of Pennsylvania Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
WO2017149515A1 (en) 2016-03-04 2017-09-08 Novartis Ag Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore
WO2017165683A1 (en) 2016-03-23 2017-09-28 Novartis Ag Cell secreted minibodies and uses thereof
US9777061B2 (en) 2014-07-21 2017-10-03 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
WO2017181119A2 (en) 2016-04-15 2017-10-19 Novartis Ag Compositions and methods for selective protein expression
CN107267619A (zh) * 2017-07-04 2017-10-20 武汉波睿达生物科技有限公司 一种检测靶向cd33的cart细胞中car表达的荧光定量试剂盒
US9815901B2 (en) 2014-08-19 2017-11-14 Novartis Ag Treatment of cancer using a CD123 chimeric antigen receptor
CN107353343A (zh) * 2017-07-04 2017-11-17 武汉波睿达生物科技有限公司 一种靶向表达cd33表面抗原的细胞的嵌合抗原受体
WO2018013918A2 (en) 2016-07-15 2018-01-18 Novartis Ag Treatment and prevention of cytokine release syndrome using a chimeric antigen receptor in combination with a kinase inhibitor
WO2018016656A1 (ja) * 2016-07-20 2018-01-25 一般社団法人 東京血液疾患研究所 骨髄異形成症候群の診断方法
WO2018023025A1 (en) 2016-07-28 2018-02-01 Novartis Ag Combination therapies of chimeric antigen receptors adn pd-1 inhibitors
WO2018026819A2 (en) 2016-08-01 2018-02-08 Novartis Ag Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule
WO2018064387A1 (en) 2016-09-28 2018-04-05 Novartis Ag Porous membrane-based macromolecule delivery system
WO2018175988A1 (en) * 2017-03-24 2018-09-27 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-cd33 immunotherapy
US10174095B2 (en) 2014-07-21 2019-01-08 Novartis Ag Nucleic acid encoding a humanized anti-BCMA chimeric antigen receptor
CN109311963A (zh) * 2016-04-14 2019-02-05 蓝鸟生物公司 救助嵌合抗原受体系统
US10221245B2 (en) 2013-03-16 2019-03-05 Novartis Ag Treatment of cancer using humanized anti-CD19 chimeric antigen receptor
US10253086B2 (en) 2015-04-08 2019-04-09 Novartis Ag CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell
WO2019079569A1 (en) 2017-10-18 2019-04-25 Novartis Ag COMPOSITIONS AND METHODS FOR SELECTIVE DEGRADATION OF A PROTEIN
US10273300B2 (en) 2014-12-29 2019-04-30 The Trustees Of The University Of Pennsylvania Methods of making chimeric antigen receptor-expressing cells
WO2019084288A1 (en) 2017-10-25 2019-05-02 Novartis Ag METHODS FOR DESIGNING CHIMERIC ANTIGENIC RECEPTOR EXPRESSION CELLS
US10287354B2 (en) 2013-12-20 2019-05-14 Novartis Ag Regulatable chimeric antigen receptor
US10308717B2 (en) 2013-02-20 2019-06-04 Novartis Ag Treatment of cancer using humanized anti-EGFRvIII chimeric antigen receptor
JP2019515652A (ja) * 2016-03-18 2019-06-13 フレッド ハッチンソン キャンサー リサーチ センター Ｃｄ２０免疫療法のための組成物および方法
WO2019116046A1 (en) * 2017-12-15 2019-06-20 Autolus Limited Cell
CN110035768A (zh) * 2016-07-26 2019-07-19 泰莎治疗私人有限公司 嵌合抗原受体
US10357514B2 (en) 2014-04-07 2019-07-23 The Trustees Of The University Of Pennsylvania Treatment of cancer using anti-CD19 Chimeric Antigen Receptor
WO2019154313A1 (zh) 2018-02-11 2019-08-15 江苏恒瑞医药股份有限公司 一种分离的嵌合抗原受体以及包含其的修饰t细胞及用途
EP3413045A4 (en) * 2016-02-09 2019-09-18 Japanese Foundation For Cancer Research DIAGNOSTIC MARKER FOR RARE HEMATOPOETIC TUMOR, TEST METHOD, THERAPEUTIC AGENT AND SCREENING METHOD
WO2019178382A1 (en) * 2018-03-14 2019-09-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-cd33 chimeric antigen receptors and their uses
WO2019177986A1 (en) * 2018-03-12 2019-09-19 Nantkwest, Inc. Use of cd33car modified high affinity nk cells (t-hank) to reduce myeloid-derived suppressor cells suppressor activity (or reduce negative impact on nk cell activity)
WO2019210153A1 (en) 2018-04-27 2019-10-31 Novartis Ag Car t cell therapies with enhanced efficacy
WO2019213282A1 (en) 2018-05-01 2019-11-07 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
WO2019227003A1 (en) 2018-05-25 2019-11-28 Novartis Ag Combination therapy with chimeric antigen receptor (car) therapies
WO2019237035A1 (en) 2018-06-08 2019-12-12 Intellia Therapeutics, Inc. Compositions and methods for immunooncology
WO2019241315A1 (en) 2018-06-12 2019-12-19 Obsidian Therapeutics, Inc. Pde5 derived regulatory constructs and methods of use in immunotherapy
CN110612109A (zh) * 2017-04-28 2019-12-24 锕医药有限责任公司 使用BCL-2抑制剂连同α-发射放射免疫治疗来治疗癌症的方法
US10525083B2 (en) 2016-10-07 2020-01-07 Novartis Ag Nucleic acid molecules encoding chimeric antigen receptors comprising a CD20 binding domain
WO2020012337A1 (en) 2018-07-10 2020-01-16 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases
US10568947B2 (en) 2014-07-21 2020-02-25 Novartis Ag Treatment of cancer using a CLL-1 chimeric antigen receptor
US10577417B2 (en) 2014-09-17 2020-03-03 Novartis Ag Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
WO2020047452A2 (en) 2018-08-31 2020-03-05 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
WO2020047449A2 (en) 2018-08-31 2020-03-05 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
WO2020056170A1 (en) * 2018-09-12 2020-03-19 Fred Hutchinson Cancer Research Center Reducing cd33 expression to selectively protect therapeutic cells
WO2020086742A1 (en) 2018-10-24 2020-04-30 Obsidian Therapeutics, Inc. Er tunable protein regulation
US10640569B2 (en) 2013-12-19 2020-05-05 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
WO2020095107A1 (en) * 2018-11-07 2020-05-14 Crispr Therapeutics Ag Anti-cd33 immune cell cancer therapy
US10660919B2 (en) 2015-10-16 2020-05-26 The Trustees Of Columbia University In The City Of New York Compositions and methods for inhibition of lineage specific antigens
WO2020123716A1 (en) 2018-12-11 2020-06-18 Obsidian Therapeutics, Inc. Membrane bound il12 compositions and methods for tunable regulation
WO2020128972A1 (en) 2018-12-20 2020-06-25 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2020165834A1 (en) 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020165833A1 (en) 2019-02-15 2020-08-20 Novartis Ag 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020176397A1 (en) 2019-02-25 2020-09-03 Novartis Ag Mesoporous silica particles compositions for viral delivery
US10774388B2 (en) 2014-10-08 2020-09-15 Novartis Ag Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
WO2020185632A1 (en) 2019-03-08 2020-09-17 Obsidian Therapeutics, Inc. Human carbonic anhydrase 2 compositions and methods for tunable regulation
EP3570850A4 (en) * 2017-01-18 2020-10-14 Thalia Papayannopoulou PACKAGING COMPOSITIONS AND METHODS FOR A TRANSPLANT RECEIVER
WO2020210678A1 (en) 2019-04-12 2020-10-15 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
JP2020530768A (ja) * 2017-07-20 2020-10-29 エイチ リー モフィット キャンサー センター アンド リサーチ インスティテュート インコーポレイテッド Ｃｄ３３発現がんを標的とするための組成物および方法
WO2020219742A1 (en) 2019-04-24 2020-10-29 Novartis Ag Compositions and methods for selective protein degradation
WO2020252405A1 (en) 2019-06-12 2020-12-17 Obsidian Therapeutics, Inc. Ca2 compositions and methods for tunable regulation
WO2020252404A1 (en) 2019-06-12 2020-12-17 Obsidian Therapeutics, Inc. Ca2 compositions and methods for tunable regulation
US10925902B2 (en) 2018-08-28 2021-02-23 Vor Biopharma, Inc Genetically engineered hematopoietic stem cells and uses thereof
AU2016342560B2 (en) * 2015-10-23 2021-03-04 Autolus Limited Receptor
WO2021046451A1 (en) 2019-09-06 2021-03-11 Obsidian Therapeutics, Inc. Compositions and methods for dhfr tunable protein regulation
WO2021108661A2 (en) 2019-11-26 2021-06-03 Novartis Ag Chimeric antigen receptors and uses thereof
US11028177B2 (en) 2013-02-20 2021-06-08 Novartis Ag Effective targeting of primary human leukemia using anti-CD123 chimeric antigen receptor engineered T cells
US11028143B2 (en) 2014-01-21 2021-06-08 Novartis Ag Enhanced antigen presenting ability of RNA CAR T cells by co-introduction of costimulatory molecules
WO2021123996A1 (en) 2019-12-20 2021-06-24 Novartis Ag Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases
WO2021173985A2 (en) 2020-02-27 2021-09-02 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
WO2021173995A2 (en) 2020-02-27 2021-09-02 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
US11161907B2 (en) 2015-02-02 2021-11-02 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
US11180553B2 (en) 2016-06-16 2021-11-23 Autolus Limited Chimeric antigen receptor
WO2021252920A1 (en) 2020-06-11 2021-12-16 Novartis Ag Zbtb32 inhibitors and uses thereof
WO2021260528A1 (en) 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2022029573A1 (en) 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2022035794A1 (en) * 2020-08-13 2022-02-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Igg4 hinge-containing chimeric antigen receptors targeting glypican-1 (gpc1) for treating solid tumors
WO2022040586A2 (en) 2020-08-21 2022-02-24 Novartis Ag Compositions and methods for in vivo generation of car expressing cells
WO2022056490A1 (en) * 2020-09-14 2022-03-17 Vor Biopharma, Inc. Chimeric antigen receptors for treatment of cancer
CN114206928A (zh) * 2019-05-08 2022-03-18 印希彼有限公司 Cd33靶向免疫疗法
WO2022140388A1 (en) 2020-12-21 2022-06-30 Allogene Therapeutics, Inc. Protease-activating cd45-gate car
WO2022165233A1 (en) 2021-01-29 2022-08-04 Allogene Therapeutics, Inc. KNOCKDOWN OR KNOCKOUT OF ONE OR MORE OF TAP2, NLRC5, β2m, TRAC, RFX5, RFXAP AND RFXANK TO MITIGATE T CELL RECOGNITION OF ALLOGENEIC CELL PRODUCTS
US11413340B2 (en) 2015-12-22 2022-08-16 Novartis Ag Mesothelin chimeric antigen receptor (CAR) and antibody against PD-L1 inhibitor for combined use in anticancer therapy
EP4043485A1 (en) 2017-01-26 2022-08-17 Novartis AG Cd28 compositions and methods for chimeric antigen receptor therapy
US11446398B2 (en) 2016-04-11 2022-09-20 Obsidian Therapeutics, Inc. Regulated biocircuit systems
US11459390B2 (en) 2015-01-16 2022-10-04 Novartis Ag Phosphoglycerate kinase 1 (PGK) promoters and methods of use for expressing chimeric antigen receptor
WO2022215011A1 (en) 2021-04-07 2022-10-13 Novartis Ag USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
EP3850011A4 (en) * 2018-09-10 2022-10-19 Nanjing Legend Biotech Co., Ltd. Single-domain antibodies against cd33 and constructs thereof
WO2022229853A1 (en) 2021-04-27 2022-11-03 Novartis Ag Viral vector production system
EP3999082A4 (en) * 2019-07-17 2022-11-30 National University of Singapore Functional binders synthesized and secreted by immune cells
US11542488B2 (en) 2014-07-21 2023-01-03 Novartis Ag Sortase synthesized chimeric antigen receptors
WO2023009712A1 (en) * 2021-07-29 2023-02-02 Ajax Therapeutics, Inc. Heteroaryloxy thiazolo azines as jak2 inhibitors
WO2023021477A1 (en) 2021-08-20 2023-02-23 Novartis Ag Methods of making chimeric antigen receptor–expressing cells
US11608382B2 (en) 2018-06-13 2023-03-21 Novartis Ag BCMA chimeric antigen receptors and uses thereof
WO2023091954A2 (en) 2021-11-19 2023-05-25 The Trustees Of The University Of Pennsylvania Engineered pan-leukocyte antigen cd45 to facilitate car t cell therapy
US11667691B2 (en) 2015-08-07 2023-06-06 Novartis Ag Treatment of cancer using chimeric CD3 receptor proteins
EP4194473A1 (en) * 2017-02-08 2023-06-14 Cellular Biomedicine Group Inc. Construction of chimeric antigen receptor targeting cd20 antigen and activity identification of engineered t cells thereof
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11725210B2 (en) 2017-03-17 2023-08-15 Fred Hutchinson Cancer Center Immunomodulatory fusion proteins and uses thereof
US11732040B2 (en) * 2017-11-27 2023-08-22 Bivictrix Limited Anti-CD33 and anti-CD7 combination treatment
US11787848B2 (en) 2016-06-08 2023-10-17 Precigen, Inc. CD33 specific chimeric antigen receptors
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
US11851659B2 (en) 2017-03-22 2023-12-26 Novartis Ag Compositions and methods for immunooncology
US11883432B2 (en) 2020-12-18 2024-01-30 Century Therapeutics, Inc. Chimeric antigen receptor system with adaptable receptor specificity
WO2024026445A1 (en) 2022-07-29 2024-02-01 Allogene Therapeutics Inc. Engineered cells with reduced gene expression to mitigate immune cell recognition
US11896614B2 (en) 2015-04-17 2024-02-13 Novartis Ag Methods for improving the efficacy and expansion of chimeric antigen receptor-expressing cells
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
WO2024089639A1 (en) 2022-10-26 2024-05-02 Novartis Ag Lentiviral formulations
US11975029B2 (en) 2017-02-28 2024-05-07 Vor Biopharma Inc. Compositions and methods for inhibition of lineage specific proteins
US11975026B2 (en) 2019-11-26 2024-05-07 Novartis Ag CD19 and CD22 chimeric antigen receptors and uses thereof
US12012443B2 (en) 2015-03-05 2024-06-18 Fred Hutchinson Cancer Center Immunomodulatory fusion proteins and uses thereof
US12037583B2 (en) 2015-12-04 2024-07-16 Novartis Ag Compositions and methods for immunooncology
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12084502B2 (en) 2019-05-04 2024-09-10 Inhibrx Biosciences, Inc. CD33-binding polypeptides and uses thereof
US12128069B2 (en) 2015-04-23 2024-10-29 The Trustees Of The University Of Pennsylvania Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
WO2024243441A1 (en) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2
EP4477748A2 (en) 2015-12-28 2024-12-18 Novartis AG Methods of making chimeric antigen receptor-expressing cells
WO2025008108A1 (en) * 2023-07-06 2025-01-09 Miltenyi Biotec B.V. & Co. KG Immune cell expressing chimeric antigen receptor and transgenic t cell receptor
US12257286B2 (en) 2018-10-31 2025-03-25 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
US12258381B2 (en) 2018-02-09 2025-03-25 National University Of Singapore Activating chimeric receptors and uses thereof in natural killer cell immunotherapy
US12264189B2 (en) 2018-10-31 2025-04-01 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
US12269859B2 (en) 2016-12-02 2025-04-08 Angeles Therapeutics, Inc. Synthetic immune receptors and methods of use thereof
US12291560B2 (en) 2018-12-14 2025-05-06 Regeneron Pharmaceuticals, Inc. Dimerizing agent regulated immunoreceptor complexes
WO2025096560A1 (en) 2023-10-30 2025-05-08 Allogene Therapeutics, Inc. Engineered cells
US12311022B2 (en) 2023-03-31 2025-05-27 AbelZeta Inc. Bispecific chimeric antigen receptors targeting CD20 and BCMA
US12383581B2 (en) 2019-10-11 2025-08-12 The Trustees Of The University Of Pennsylvania Compositions and methods for targeting CD13 and TIM-3 with CAR T cells to treat acute myeloid leukemia
US12398187B2 (en) 2019-03-05 2025-08-26 Nkarta, Inc. CD19-directed chimeric antigen receptors and uses thereof in immunotherapy
US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof
US12441787B2 (en) 2018-04-02 2025-10-14 National University Of Singapore Neutralization of human cytokines with membrane-bound anti-cytokine non-signaling binders expressed in immune cells
US12448432B2 (en) 2020-03-17 2025-10-21 AbelZeta Inc. Combined chimeric antigen receptor targeting CD19 and CD20 and application thereof
US12509455B2 (en) 2019-11-07 2025-12-30 Dana-Farber Cancer Institute, Inc. Imidazopyridine derivatives and aza-imidazopyridine derivatives as Janus kinase 2 inhibitors and uses thereof

Families Citing this family (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2817331B1 (en) 2012-02-22 2023-08-30 The Trustees of the University of Pennsylvania Use of the cd2 signaling domain in second-generation chimeric antigen receptors
ES2776698T3 (es) 2012-12-20 2020-07-31 Purdue Research Foundation Células T que expresan un receptor antigénico quimérico como terapia contra el cáncer
US20150140036A1 (en) * 2013-11-13 2015-05-21 Novartis Institutes For Biomedical Research, Inc. Low, immune enhancing, dose mtor inhibitors and uses thereof
HK1245095A1 (zh) 2015-05-20 2018-08-24 Novartis Ag 依维莫司(everolimus)与达托里昔布(dactolisib)的医药组合
JP7282521B2 (ja) 2016-04-08 2023-05-29 パーデュー・リサーチ・ファウンデイション Ｃａｒ ｔ細胞療法のための方法および組成物
EP4413999A3 (en) * 2016-05-27 2024-08-28 The United States of America, as represented by the Secretary, Department of Health and Human Services Flt3-specific chimeric antigen receptors and methods using same
WO2017210621A1 (en) * 2016-06-03 2017-12-07 Seattle Genetics, Inc. Combination of cd33 antibody drug conjugates with chemotherapeutic agents
EP3469001A4 (en) * 2016-06-09 2020-05-06 Seattle Genetics, Inc. COMBINATIONS OF PBD-BASED ANTIBODY CONJUGATES WITH FLT3 INHIBITORS
US11384156B2 (en) 2016-07-25 2022-07-12 The Nemours Foundation Adoptive T-cell therapy using EMPD-specific chimeric antigen receptors for treating IgE-mediated allergic diseases
ES2981703T3 (es) * 2016-09-02 2024-10-10 Lentigen Tech Inc Composiciones y métodos para tratar cáncer con DuoCars
WO2018096402A1 (en) 2016-11-23 2018-05-31 Novartis Ag Methods of enhancing immune response with everolimus, dactolisib or both
US11649288B2 (en) 2017-02-07 2023-05-16 Seattle Children's Hospital Phospholipid ether (PLE) CAR T cell tumor targeting (CTCT) agents
CA3221995C (en) 2017-02-08 2024-05-28 Dragonfly Therapeutics, Inc. Multi-specific binding proteins for activation of natural killer cells and therapeutic uses thereof to treat cancer
SG11201907646YA (en) 2017-02-20 2019-09-27 Dragonfly Therapeutics Inc Proteins binding her2, nkg2d and cd16
WO2018160622A1 (en) 2017-02-28 2018-09-07 Endocyte, Inc. Compositions and methods for car t cell therapy
CA3057505A1 (en) 2017-03-31 2018-10-04 The Board Of Trustees Of The Leland Stanford Junior University Methods of treating t cell exhaustion by inhibiting or modulating t cell receptor signaling
AU2018256436B2 (en) 2017-04-19 2024-12-05 Board Of Regents, The University Of Texas System Immune cells expressing engineered antigen receptors
AU2018269194B2 (en) * 2017-05-15 2025-05-22 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Bicistronic chimeric antigen receptors and their uses
US12116406B2 (en) 2017-05-26 2024-10-15 Fred Hutchinson Cancer Center Anti-CD33 antibodies and uses thereof
WO2019046285A1 (en) * 2017-08-28 2019-03-07 The Trustees Of Columbia University In The City Of New York CD33 EXON 2 DONOR STEM CELLS FOR USE WITH CD33 TARGETING AGENTS
WO2019056174A1 (zh) * 2017-09-19 2019-03-28 中山大学 一种过表达cxcr5的间质干细胞及其制备方法和用途
WO2019084234A1 (en) * 2017-10-26 2019-05-02 St. Jude Childen's Research Hospital, Inc. METHODS AND COMPOSITIONS FOR TREATING CD33 + CANCERS AND IMPROVING IN VIVO PERSISTENCE OF CHIMERIC ANTIGEN RECEPTOR T CELLS
WO2019090244A2 (en) * 2017-11-03 2019-05-09 Health Research, Inc. Myeloid-derived suppressor cell cluster analysis in vitro
ES3039245T3 (en) * 2017-11-10 2025-10-20 Actinium Pharmaceuticals Inc Combination of radionuclide-conjugated antibodies for treatment of a hematological malignancies
JP2021508246A (ja) * 2017-12-21 2021-03-04 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト 新規抗原結合部分の特異性試験のためのｃａｒ−ｔ細胞アッセイ
MX2020006843A (es) 2017-12-27 2020-09-03 Takeda Pharmaceuticals Co Nanoparticula de lipido que contiene acido nucleico y uso de la misma.
CN112292138A (zh) 2018-01-22 2021-01-29 西雅图儿童医院（Dba西雅图儿童研究所） Car t细胞的使用方法
SG11202007426XA (en) 2018-02-06 2020-09-29 Seattle Childrens Hospital Dba Seattle Childrens Res Inst Fluorescein-specific cars exhibiting optimal t cell function against fl-ple labelled tumors
KR20200118824A (ko) 2018-02-08 2020-10-16 드래곤플라이 쎄라퓨틱스, 인크. 자연 살해 세포를 활성화시키는 다중-특이성 결합 단백질을 수반하는 암의 병용 요법
PT3749346T (pt) 2018-02-08 2024-09-05 Dragonfly Therapeutics Inc Combinações de domínios variáveis de anticorpos dirigidas ao receptor nkg2d
CN110157678A (zh) * 2018-02-12 2019-08-23 深圳宾德生物技术有限公司 一种靶向性t淋巴细胞及其制备方法和应用
CN110157674A (zh) * 2018-02-12 2019-08-23 深圳宾德生物技术有限公司 一种靶向性t淋巴细胞及其制备方法和应用
CA3091424A1 (en) 2018-02-20 2019-08-29 Dragonfly Therapeutics, Inc. Multi-specific binding proteins that bind cd33, nkg2d, and cd16, and methods of use
EP3755349A4 (en) 2018-02-21 2021-11-17 Board of Regents, The University of Texas System PROCESS FOR ACTIVATION AND EXPANSION OF NATURAL KILLER CELLS AND THEIR USES
WO2019165237A1 (en) 2018-02-23 2019-08-29 Endocyte, Inc. Sequencing method for car t cell therapy
WO2019195596A1 (en) 2018-04-06 2019-10-10 The Regents Of The University Of California Methods of treating glioblastomas
WO2019195586A1 (en) 2018-04-06 2019-10-10 The Regents Of The University Of California Methods of treating egfrviii expressing glioblastomas
CN110551741A (zh) * 2018-06-01 2019-12-10 上海恒润达生生物科技有限公司 靶向cd33的嵌合抗原受体及其用途
CA3108646A1 (en) 2018-08-08 2020-02-13 Dragonfly Therapeutics, Inc. Proteins binding nkg2d, cd16 and a tumor-associated antigen
AU2019318083A1 (en) 2018-08-08 2021-02-25 Dragonfly Therapeutics, Inc. Multi-specific binding proteins that bind BCMA, NKG2D and CD16, and methods of use
EA202091888A1 (ru) 2018-08-08 2020-10-23 Драгонфлай Терапьютикс, Инк. Вариабельные домены антител, нацеленные на рецептор nkg2d
EP3845654A4 (en) 2018-08-31 2022-05-11 Noile-Immune Biotech, Inc. Car-expressing t cells and car expression vector
CN109265561B (zh) * 2018-09-25 2021-05-25 山东兴瑞生物科技有限公司 抗EGFRvⅢ安全型嵌合抗原受体、其制备方法、利用其修饰的NK细胞及应用
US12331320B2 (en) 2018-10-10 2025-06-17 The Research Foundation For The State University Of New York Genome edited cancer cell vaccines
EP3873539A4 (en) * 2018-10-31 2023-01-18 The Children's Hospital of Philadelphia LYMPH-BASED T-CELLS FOR DIAGNOSTIC AND THERAPEUTIC USE
US20220088075A1 (en) 2019-02-22 2022-03-24 The Trustees Of The University Of Pennsylvania Combination therapies of egfrviii chimeric antigen receptors and pd-1 inhibitors
WO2020205604A1 (en) 2019-03-29 2020-10-08 Salk Institute For Biological Studies High-efficiency reconstitution of rna molecules
WO2020210719A1 (en) 2019-04-10 2020-10-15 Elevatebio Management, Inc. Flt3-specific chimeric antigen receptors and methods of using the same
WO2020215044A1 (en) * 2019-04-17 2020-10-22 The Regents Of The University Of California Small molecule-based control of immune cell receptor expression
US20220195441A1 (en) * 2019-04-25 2022-06-23 Seattle Children's Hospital (dba Seattle Children's Research Institute) Combinatorial car t cell and hematopoeitic stem cell genetic engineering for specific immunotherapy of myeloid leukemias
SG11202111130SA (en) * 2019-04-30 2021-11-29 Senti Biosciences Inc Chimeric receptors and methods of use thereof
EP3990022A4 (en) * 2019-06-26 2023-06-28 Memorial Sloan Kettering Cancer Center Anti-cd33 antibodies for treating cancer
EP3991746A4 (en) 2019-06-26 2023-08-09 Takeda Pharmaceutical Company Limited TRANSFECTION METHOD
GB201909283D0 (en) 2019-06-27 2019-08-14 Cancer Research Tech Ltd Fusion proteins with enzyme activity
CN113493518B (zh) * 2020-04-02 2024-04-19 重庆精准生物技术有限公司 优化的连接肽组合及其应用
MX2022013944A (es) 2020-05-06 2022-11-30 Dragonfly Therapeutics Inc Proteinas que se unen al receptor activador de celulas asesinas naturales grupo 2 miembro d (nkg2d), cumulo de diferenciacion (cd16) y miembro a de la familia de dominios de lectina tipo c 12 (clec12a).
GB202018554D0 (en) 2020-11-25 2021-01-06 Cancer Research Tech Ltd Nucleic acid constructs and cells
JP2024508894A (ja) 2021-03-03 2024-02-28 ドラゴンフライ セラピューティクス， インコーポレイテッド Ｎｋｇ２ｄ、ｃｄ１６、及び腫瘍関連抗原に結合する多特異性結合タンパク質を使用して癌を治療する方法
CN117580863A (zh) * 2021-09-01 2024-02-20 中国科学院生物物理研究所 嵌合抗原受体及其用途
WO2023034560A1 (en) * 2021-09-02 2023-03-09 Memorial Sloan-Kettering Cancer Center Antigen recognizing receptors targeting cd33 and uses thereof
WO2024020596A1 (en) * 2022-07-22 2024-01-25 Villanova University Methods and compositions comprising fusion proteins for the identification of immunotherapy cells
WO2024059733A2 (en) * 2022-09-14 2024-03-21 Fred Hutchinson Cancer Center Chimeric antigen receptors binding nectin-4
TW202530421A (zh) * 2022-10-28 2025-08-01 美商凱特製藥公司 用於將免疫療法最佳化之因素
WO2024103049A1 (en) * 2022-11-11 2024-05-16 The United States Government As Represented By The Department Of Veterans Affairs Cd33 specific exosomes and uses thereof
TW202449142A (zh) 2023-04-07 2024-12-16 日商武田藥品工業股份有限公司 接合複合物
WO2024249925A1 (en) * 2023-06-01 2024-12-05 Research Institute At Nationwide Children's Hospital Cd-33 protein-binding compositions and methods related thereto
WO2025090985A1 (en) * 2023-10-27 2025-05-01 Duke University Compositions comprising chimeric antigen receptors targeting citrullinated vimentin and methods of use thereof
WO2025151706A1 (en) * 2024-01-12 2025-07-17 Board Of Regents, The University Of Texas System Epigenetic reagents and utilization of car nk cells

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015090229A1 (en) * 2013-12-20 2015-06-25 Novartis Ag Regulatable chimeric antigen receptor

Family Cites Families (393)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA737247B (en) 1972-09-29 1975-04-30 Ayerst Mckenna & Harrison Rapamycin and process of preparation
US4433059A (en) 1981-09-08 1984-02-21 Ortho Diagnostic Systems Inc. Double antibody conjugate
US4444878A (en) 1981-12-21 1984-04-24 Boston Biomedical Research Institute, Inc. Bispecific antibody determinants
EP0090505B1 (en) 1982-03-03 1990-08-08 Genentech, Inc. Human antithrombin iii, dna sequences therefor, expression vehicles and cloning vectors containing such sequences and cell cultures transformed thereby, a process for expressing human antithrombin iii, and pharmaceutical compositions comprising it
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US6548640B1 (en) 1986-03-27 2003-04-15 Btg International Limited Altered antibodies
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
US5869620A (en) 1986-09-02 1999-02-09 Enzon, Inc. Multivalent antigen-binding proteins
US5906936A (en) 1988-05-04 1999-05-25 Yeda Research And Development Co. Ltd. Endowing lymphocytes with antibody specificity
JPH021556A (ja) 1988-06-09 1990-01-05 Snow Brand Milk Prod Co Ltd ハイブリッド抗体及びその作製方法
DE68927933T2 (de) 1988-09-02 1997-08-14 Dyax Corp Herstellung und auswahl von rekombinantproteinen mit verschiedenen bindestellen
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US6303121B1 (en) 1992-07-30 2001-10-16 Advanced Research And Technology Method of using human receptor protein 4-1BB
US5858358A (en) 1992-04-07 1999-01-12 The United States Of America As Represented By The Secretary Of The Navy Methods for selectively stimulating proliferation of T cells
US6905680B2 (en) 1988-11-23 2005-06-14 Genetics Institute, Inc. Methods of treating HIV infected subjects
US6352694B1 (en) 1994-06-03 2002-03-05 Genetics Institute, Inc. Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells
US6534055B1 (en) 1988-11-23 2003-03-18 Genetics Institute, Inc. Methods for selectively stimulating proliferation of T cells
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5703055A (en) 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
US5399346A (en) 1989-06-14 1995-03-21 The United States Of America As Represented By The Department Of Health And Human Services Gene therapy
DE3920358A1 (de) 1989-06-22 1991-01-17 Behringwerke Ag Bispezifische und oligospezifische, mono- und oligovalente antikoerperkonstrukte, ihre herstellung und verwendung
US5585362A (en) 1989-08-22 1996-12-17 The Regents Of The University Of Michigan Adenovirus vectors for gene therapy
WO1991003493A1 (en) 1989-08-29 1991-03-21 The University Of Southampton Bi-or trispecific (fab)3 or (fab)4 conjugates
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
US5273743A (en) 1990-03-09 1993-12-28 Hybritech Incorporated Trifunctional antibody-like compounds as a combined diagnostic and therapeutic agent
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
GB9012995D0 (en) 1990-06-11 1990-08-01 Celltech Ltd Multivalent antigen-binding proteins
AU665190B2 (en) 1990-07-10 1995-12-21 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
DK0564531T3 (da) 1990-12-03 1998-09-28 Genentech Inc Berigelsesfremgangsmåde for variantproteiner med ændrede bindingsegenskaber
US5582996A (en) 1990-12-04 1996-12-10 The Wistar Institute Of Anatomy & Biology Bifunctional antibodies and method of preparing same
US6319494B1 (en) 1990-12-14 2001-11-20 Cell Genesys, Inc. Chimeric chains for receptor-associated signal transduction pathways
AU643109B2 (en) 1990-12-14 1993-11-04 Cell Genesys, Inc. Chimeric chains for receptor-associated signal transduction pathways
DK1279731T3 (da) 1991-03-01 2007-09-24 Dyax Corp Fremgangsmåde til udvikling af bindende miniproteiner
US7049136B2 (en) 1991-03-07 2006-05-23 The General Hospital Corporation Redirection of cellular immunity by receptor chimeras
US6004811A (en) 1991-03-07 1999-12-21 The Massachussetts General Hospital Redirection of cellular immunity by protein tyrosine kinase chimeras
IL101147A (en) 1991-03-07 2004-06-20 Gen Hospital Corp Redirection of cellular immunity by receptor chimeras
DK1471142T3 (da) 1991-04-10 2009-03-09 Scripps Research Inst Heterodimere receptor-biblioteker under anvendelse af fagemider
DE69233482T2 (de) 1991-05-17 2006-01-12 Merck & Co., Inc. Verfahren zur Verminderung der Immunogenität der variablen Antikörperdomänen
DE4118120A1 (de) 1991-06-03 1992-12-10 Behringwerke Ag Tetravalente bispezifische rezeptoren, ihre herstellung und verwendung
US5199942A (en) 1991-06-07 1993-04-06 Immunex Corporation Method for improving autologous transplantation
US6511663B1 (en) 1991-06-11 2003-01-28 Celltech R&D Limited Tri- and tetra-valent monospecific antigen-binding proteins
CA2103059C (en) 1991-06-14 2005-03-22 Paul J. Carter Method for making humanized antibodies
US5637481A (en) 1993-02-01 1997-06-10 Bristol-Myers Squibb Company Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell
DE4122599C2 (de) 1991-07-08 1993-11-11 Deutsches Krebsforsch Phagemid zum Screenen von Antikörpern
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
US5932448A (en) 1991-11-29 1999-08-03 Protein Design Labs., Inc. Bispecific antibody heterodimers
GB9125768D0 (en) 1991-12-04 1992-02-05 Hale Geoffrey Therapeutic method
EP1291360A1 (en) 1991-12-13 2003-03-12 Xoma Corporation Methods and materials for preparation of modified antibody variable domains and therapeutic uses thereof
US5910573A (en) 1992-01-23 1999-06-08 Merck Patent Gesellschaft Mit Beschrankter Haftung Monomeric and dimeric antibody-fragment fusion proteins
DE69333807T2 (de) 1992-02-06 2006-02-02 Chiron Corp., Emeryville Marker für krebs und biosynthetisches bindeprotein dafür
GB9203459D0 (en) 1992-02-19 1992-04-08 Scotgen Ltd Antibodies with germ-line variable regions
IL104570A0 (en) 1992-03-18 1993-05-13 Yeda Res & Dev Chimeric genes and cells transformed therewith
US8211422B2 (en) 1992-03-18 2012-07-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Chimeric receptor genes and cells transformed therewith
AU675223B2 (en) 1992-05-08 1997-01-30 Creative Biomolecules, Inc. Chimeric multivalent protein analogues and methods of use thereof
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
ATE427968T1 (de) 1992-08-21 2009-04-15 Univ Bruxelles Immunoglobuline ohne leichtkette
US5350674A (en) 1992-09-04 1994-09-27 Becton, Dickinson And Company Intrinsic factor - horse peroxidase conjugates and a method for increasing the stability thereof
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
DE69334287D1 (de) 1992-09-25 2009-07-09 Avipep Pty Ltd Zielmoleküle-bindende Polypeptide bestehend aus einer IG-artigen VL Domäne die an eine IG-artige VH Domäne gebunden ist
GB9221220D0 (en) 1992-10-09 1992-11-25 Sandoz Ag Organic componds
GB9221657D0 (en) 1992-10-15 1992-11-25 Scotgen Ltd Recombinant bispecific antibodies
WO1994009817A1 (en) 1992-11-04 1994-05-11 City Of Hope Novel antibody construct
GB9323648D0 (en) 1992-11-23 1994-01-05 Zeneca Ltd Proteins
ATE199392T1 (de) 1992-12-04 2001-03-15 Medical Res Council Multivalente und multispezifische bindungsproteine, deren herstellung und verwendung
US7211259B1 (en) 1993-05-07 2007-05-01 Immunex Corporation 4-1BB polypeptides and DNA encoding 4-1BB polypeptides
US6476198B1 (en) 1993-07-13 2002-11-05 The Scripps Research Institute Multispecific and multivalent antigen-binding polypeptide molecules
US5635602A (en) 1993-08-13 1997-06-03 The Regents Of The University Of California Design and synthesis of bispecific DNA-antibody conjugates
WO1995009917A1 (en) 1993-10-07 1995-04-13 The Regents Of The University Of California Genetically engineered bispecific tetravalent antibodies
CA2175215C (en) 1993-11-19 2008-06-03 Yat Sun Or Semisynthetic analogs of rapamycin (macrolides) being immunomodulators
ATE191218T1 (de) 1993-12-17 2000-04-15 Novartis Ag Rapamycin-derivate als immunosuppressoren
US5362718A (en) 1994-04-18 1994-11-08 American Home Products Corporation Rapamycin hydroxyesters
NZ285395A (en) 1994-05-02 1998-10-28 Novartis Ag Chimeric antibody, cancer treatment
US7175843B2 (en) 1994-06-03 2007-02-13 Genetics Institute, Llc Methods for selectively stimulating proliferation of T cells
US5786464C1 (en) 1994-09-19 2012-04-24 Gen Hospital Corp Overexpression of mammalian and viral proteins
EP0787185A2 (en) 1994-10-20 1997-08-06 MorphoSys AG Targeted hetero-association of recombinant proteins to multi-functional complexes
US5712149A (en) 1995-02-03 1998-01-27 Cell Genesys, Inc. Chimeric receptor molecules for delivery of co-stimulatory signals
US6103521A (en) 1995-02-06 2000-08-15 Cell Genesys, Inc. Multispecific chimeric receptors
KR100490099B1 (ko) 1995-02-24 2005-11-28 더 제너럴 하스피털 코포레이션 수용체키메라에의한세포면역성의방향전환
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
US7067318B2 (en) 1995-06-07 2006-06-27 The Regents Of The University Of Michigan Methods for transfecting T cells
US6692964B1 (en) 1995-05-04 2004-02-17 The United States Of America As Represented By The Secretary Of The Navy Methods for transfecting T cells
DE69633175T2 (de) 1995-05-23 2005-08-11 Morphosys Ag Multimere proteine
DK0833828T3 (da) 1995-06-09 2003-03-17 Novartis Ag Rapamycinderivater
BE1009856A5 (fr) 1995-07-14 1997-10-07 Sandoz Sa Composition pharmaceutique sous la forme d'une dispersion solide comprenant un macrolide et un vehicule.
WO1997014719A1 (en) 1995-10-16 1997-04-24 Unilever N.V. A bifunctional or bivalent antibody fragment analogue
GB9526131D0 (en) 1995-12-21 1996-02-21 Celltech Therapeutics Ltd Recombinant chimeric receptors
US5874240A (en) 1996-03-15 1999-02-23 Human Genome Sciences, Inc. Human 4-1BB receptor splicing variant
JP2000508892A (ja) 1996-04-04 2000-07-18 ユニリーバー・ナームローゼ・ベンノートシャープ 多価および多特異的抗原結合タンパク
US6258823B1 (en) 1996-07-12 2001-07-10 Ariad Pharmaceuticals, Inc. Materials and method for treating or preventing pathogenic fungal infection
CA2263129C (en) 1996-08-16 2007-01-09 Schering Corporation Mammalian cell surface antigens; related reagents
US6111090A (en) 1996-08-16 2000-08-29 Schering Corporation Mammalian cell surface antigens; related reagents
US6114148C1 (en) 1996-09-20 2012-05-01 Gen Hospital Corp High level expression of proteins
EP0937095A4 (en) 1996-10-25 1999-12-22 Cell Genesys Inc TARGETED CYTOLYSIS OF CANCER CELLS
PT1712623E (pt) 1997-01-21 2011-12-21 Gen Hospital Corp Selecção de proteínas utilizando fusões de arn-proteína
WO1998048837A1 (en) 1997-04-30 1998-11-05 Enzon, Inc. Polyalkylene oxide-modified single chain polypeptides
US20030207346A1 (en) 1997-05-02 2003-11-06 William R. Arathoon Method for making multispecific antibodies having heteromultimeric and common components
US20020062010A1 (en) 1997-05-02 2002-05-23 Genentech, Inc. Method for making multispecific antibodies having heteromultimeric and common components
WO1998056906A1 (en) 1997-06-11 1998-12-17 Thoegersen Hans Christian Trimerising module
ATE386802T1 (de) 1997-06-12 2008-03-15 Novartis Int Pharm Ltd Künstliche antikörperpolypeptide
US20030060444A1 (en) 1997-06-25 2003-03-27 Celltech Therapeutics, Ltd. Cell activation process and reagents therefor
GB9713473D0 (en) 1997-06-25 1997-09-03 Celltech Therapeutics Ltd Biological products
US6015815A (en) 1997-09-26 2000-01-18 Abbott Laboratories Tetrazole-containing rapamycin analogs with shortened half-lives
TW557297B (en) 1997-09-26 2003-10-11 Abbott Lab Rapamycin analogs having immunomodulatory activity, and pharmaceutical compositions containing same
AU1102399A (en) 1997-10-21 1999-05-10 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like proteins tr11, tr11sv1, and tr11sv2
CN1203178C (zh) 1997-10-27 2005-05-25 尤尼利弗公司 多价抗原结合蛋白
WO1999037791A1 (en) 1998-01-23 1999-07-29 Vlaams Interuniversitair Instituut Voor Biotechnologie Multipurpose antibody derivatives
EP1053321A1 (en) 1998-02-09 2000-11-22 Genentech, Inc. Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same
HUP9900956A2 (hu) 1998-04-09 2002-04-29 Aventis Pharma Deutschland Gmbh. Egyláncú, több antigéntkötőhely kialakítására képes molekulák, előállításuk és alkalmazásuk
WO1999052552A1 (en) 1998-04-15 1999-10-21 Brigham & Women's Hospital, Inc. T cell inhibitory receptor compositions and uses thereof
DE19819846B4 (de) 1998-05-05 2016-11-24 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Multivalente Antikörper-Konstrukte
GB9809658D0 (en) 1998-05-06 1998-07-01 Celltech Therapeutics Ltd Biological products
GB9812545D0 (en) 1998-06-10 1998-08-05 Celltech Therapeutics Ltd Biological products
AU5728999A (en) 1998-07-28 2000-02-21 Micromet Ag Heterominibodies
JP2002524081A (ja) 1998-09-04 2002-08-06 スローン − ケッタリング インスティチュート フォー キャンサー リサーチ 前立腺−特異的膜抗原に特異的な融合受容体およびその使用
US6333396B1 (en) 1998-10-20 2001-12-25 Enzon, Inc. Method for targeted delivery of nucleic acids
US6410319B1 (en) 1998-10-20 2002-06-25 City Of Hope CD20-specific redirected T cells and their use in cellular immunotherapy of CD20+ malignancies
EP1171596A1 (en) 1999-04-16 2002-01-16 Celltech Therapeutics Limited Synthetic transmembrane components
US7534866B2 (en) 2005-10-19 2009-05-19 Ibc Pharmaceuticals, Inc. Methods and compositions for generating bioactive assemblies of increased complexity and uses
US7527787B2 (en) 2005-10-19 2009-05-05 Ibc Pharmaceuticals, Inc. Multivalent immunoglobulin-based bioactive assemblies
ES2295040T3 (es) 1999-07-12 2008-04-16 Genentech, Inc. Promocion o inhibicion de la angiogenesis y cardiovascularizacion mediante homologos del ligando / receptor del factor de necrosis del tumor.
AU783158B2 (en) 1999-08-24 2005-09-29 Ariad Pharmaceuticals, Inc. 28-epirapalogs
JP2003516124A (ja) 1999-10-15 2003-05-13 ユニバーシティー オブ マサチューセッツ 標的とした遺伝的干渉の手段としてのｒｎａ干渉経路遺伝子
GB9925848D0 (en) 1999-11-01 1999-12-29 Celltech Therapeutics Ltd Biological products
US6326193B1 (en) 1999-11-05 2001-12-04 Cambria Biosciences, Llc Insect control agent
AU2001243288B2 (en) 2000-02-24 2005-11-24 Life Technologies Corporation Simultaneous stimulation and concentration of cells
US6797514B2 (en) 2000-02-24 2004-09-28 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
US6867041B2 (en) 2000-02-24 2005-03-15 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
US7572631B2 (en) 2000-02-24 2009-08-11 Invitrogen Corporation Activation and expansion of T cells
MXPA02010011A (es) 2000-04-11 2003-04-25 Genentech Inc Anticuerpos multivalentes y usos para los mismos.
WO2001090192A2 (en) 2000-05-24 2001-11-29 Imclone Systems Incorporated Bispecific immunoglobulin-like antigen binding proteins and method of production
IL136511A0 (en) 2000-06-01 2001-06-14 Gavish Galilee Bio Appl Ltd Genetically engineered mhc molecules
AU2001275474A1 (en) 2000-06-12 2001-12-24 Akkadix Corporation Materials and methods for the control of nematodes
EP1294904A1 (en) 2000-06-30 2003-03-26 Vlaams Interuniversitair Instituut voor Biotechnologie vzw. Heterodimeric fusion proteins
JP2004523205A (ja) 2000-07-25 2004-08-05 イムノメディクス， インコーポレイテッド 多価標的結合タンパク質
GB0025307D0 (en) 2000-10-16 2000-11-29 Celltech Chiroscience Ltd Biological products
EP2351838A1 (en) 2000-10-20 2011-08-03 Chugai Seiyaku Kabushiki Kaisha Crosslinking agonistic antibodies
JP5312721B2 (ja) 2000-11-07 2013-10-09 シティ・オブ・ホープ Ｃｄ１９特異的再指向免疫細胞
US7829084B2 (en) 2001-01-17 2010-11-09 Trubion Pharmaceuticals, Inc. Binding constructs and methods for use thereof
WO2002072635A2 (en) 2001-03-13 2002-09-19 University College London Specific binding members
US7070995B2 (en) 2001-04-11 2006-07-04 City Of Hope CE7-specific redirected immune cells
CN1294148C (zh) 2001-04-11 2007-01-10 中国科学院遗传与发育生物学研究所 环状单链三特异抗体
US20090257994A1 (en) 2001-04-30 2009-10-15 City Of Hope Chimeric immunoreceptor useful in treating human cancers
US7514537B2 (en) 2001-04-30 2009-04-07 City Of Hope Chimeric immunoreceptor useful in treating human gliomas
EP1392818A4 (en) 2001-04-30 2005-01-05 Hope City FOR THE TREATMENT OF CANCER DISEASES IN HUMAN CERTAIN IMMUNE RECEPTOR
CA2447851C (en) 2001-06-28 2012-08-28 Domantis Limited Dual-specific ligand and its use
US6833441B2 (en) 2001-08-01 2004-12-21 Abmaxis, Inc. Compositions and methods for generating chimeric heteromultimers
ES2337986T3 (es) 2001-08-10 2010-05-03 Aberdeen University Dominios de union de antigenos de peces.
DE60124912T2 (de) 2001-09-14 2007-06-14 Affimed Therapeutics Ag Multimerische, einzelkettige, Tandem-Fv-Antikörper
US20030186374A1 (en) 2001-10-01 2003-10-02 Hufton Simon E. Multi-chain eukaryotic display vectors and uses thereof
US20030148982A1 (en) 2001-11-13 2003-08-07 Brenner Malcolm K. Bi-spcific chimeric T cells
AU2002357072A1 (en) 2001-12-07 2003-06-23 Centocor, Inc. Pseudo-antibody constructs
US7745140B2 (en) 2002-01-03 2010-06-29 The Trustees Of The University Of Pennsylvania Activation and expansion of T-cells using an engineered multivalent signaling platform as a research tool
AU2003202908A1 (en) 2002-01-03 2003-07-24 The Trustees Of The University Of Pennsylvania Activation and expansion of t-cells using an engineered multivalent signaling platform
US7638326B2 (en) 2002-01-03 2009-12-29 The Trustees Of The University Of Pennsylvania Activation and expansion of T-cells using an engineered multivalent signaling platform
WO2003064383A2 (en) 2002-02-01 2003-08-07 Ariad Gene Therapeutics, Inc. Phosphorus-containing compounds & uses thereof
JP2006502091A (ja) 2002-03-01 2006-01-19 イミューノメディクス、インコーポレイテッド クリアランス速度を高めるための二重特異性抗体点変異
GB0208104D0 (en) 2002-04-09 2002-05-22 Univ Dundee Method
AU2003227504A1 (en) 2002-04-15 2003-10-27 Chugai Seiyaku Kabushiki Kaisha METHOD OF CONSTRUCTING scDb LIBRARY
US7446190B2 (en) 2002-05-28 2008-11-04 Sloan-Kettering Institute For Cancer Research Nucleic acids encoding chimeric T cell receptors
US20040047858A1 (en) 2002-09-11 2004-03-11 Blumberg Richard S. Therapeutic anti-BGP(C-CAM1) antibodies and uses thereof
SI1578446T1 (sl) * 2002-11-07 2015-07-31 Immunogen, Inc. Protitelesa proti-cd33 in metoda za zdravljenje akutne mieloidne levkemije z uporabo istega
ES2367430T3 (es) 2002-12-23 2011-11-03 Wyeth Llc Anticuerpos contra pd-1 y sus usos.
GB0230203D0 (en) 2002-12-27 2003-02-05 Domantis Ltd Fc fusion
US20050129671A1 (en) 2003-03-11 2005-06-16 City Of Hope Mammalian antigen-presenting T cells and bi-specific T cells
GB0305702D0 (en) 2003-03-12 2003-04-16 Univ Birmingham Bispecific antibodies
EP1618181B1 (en) 2003-04-22 2014-10-15 IBC Pharmaceuticals Polyvalent protein complex
JP4638876B2 (ja) 2003-05-23 2011-02-23 ワイス Ｇｉｔｒリガンド及びｇｉｔｒリガンド関連分子及び抗体及びその使用
AU2004252170B2 (en) 2003-06-27 2011-01-27 Biogen Ma Inc. Use of hydrophobic-interaction-chromatography or hinge-region modifications for the production of homogeneous antibody-solutions
CA2531118C (en) 2003-07-01 2013-01-08 Immunomedics, Inc. Multivalent carriers of bi-specific antibodies
WO2005007190A1 (en) 2003-07-11 2005-01-27 Schering Corporation Agonists or antagonists of the clucocorticoid-induced tumour necrosis factor receptor (gitr) or its ligand for the treatment of immune disorders, infections and cancer
US7696322B2 (en) 2003-07-28 2010-04-13 Catalent Pharma Solutions, Inc. Fusion antibodies
CA2536238C (en) 2003-08-18 2015-04-07 Medimmune, Inc. Humanization of antibodies
WO2005019429A2 (en) 2003-08-22 2005-03-03 Potentia Pharmaceuticals, Inc. Compositions and methods for enhancing phagocytosis or phagocyte activity
WO2005035575A2 (en) 2003-08-22 2005-04-21 Medimmune, Inc. Humanization of antibodies
CA2542046A1 (en) 2003-10-08 2005-04-21 Kyowa Hakko Kogyo Co., Ltd. Fused protein composition
US20050113564A1 (en) 2003-11-05 2005-05-26 St. Jude Children's Research Hospital Chimeric receptors with 4-1BB stimulatory signaling domain
US7435596B2 (en) 2004-11-04 2008-10-14 St. Jude Children's Research Hospital, Inc. Modified cell line and method for expansion of NK cell
US7220755B2 (en) 2003-11-12 2007-05-22 Biosensors International Group, Ltd. 42-O-alkoxyalkyl rapamycin derivatives and compositions comprising same
JP2007518399A (ja) 2003-12-02 2007-07-12 ジェンザイム コーポレイション 肺癌を診断および治療する組成物並びに方法
WO2005062916A2 (en) 2003-12-22 2005-07-14 Centocor, Inc. Methods for generating multimeric molecules
GB0329825D0 (en) 2003-12-23 2004-01-28 Celltech R&D Ltd Biological products
US20050266425A1 (en) 2003-12-31 2005-12-01 Vaccinex, Inc. Methods for producing and identifying multispecific antibodies
US8383575B2 (en) 2004-01-30 2013-02-26 Paul Scherrer Institut (DI)barnase-barstar complexes
GB0409799D0 (en) 2004-04-30 2004-06-09 Isis Innovation Method of generating improved immune response
WO2005118788A2 (en) 2004-05-27 2005-12-15 The Trustees Of The University Of Pennsylvania Novel artificial antigen presenting cells and uses therefor
EP1765402A2 (en) 2004-06-04 2007-03-28 Duke University Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity
JP2008512352A (ja) 2004-07-17 2008-04-24 イムクローン システムズ インコーポレイティド 新規な四価の二重特異性抗体
US20060204493A1 (en) 2004-09-02 2006-09-14 Genentech, Inc. Heteromultimeric molecules
US7994298B2 (en) 2004-09-24 2011-08-09 Trustees Of Dartmouth College Chimeric NK receptor and methods for treating cancer
EP1827604B1 (en) 2004-12-10 2019-11-20 Peter MacCallum Cancer Institute Methods and compositions for adoptive immunotherapy
RU2436575C2 (ru) * 2005-01-21 2011-12-20 Астекс Терапьютикс Лимитед Соединения для использования в фармацевтике
DK1866339T3 (da) 2005-03-25 2013-09-02 Gitr Inc GTR-bindende molekyler og anvendelser heraf
JP5620626B2 (ja) 2005-03-31 2014-11-05 中外製薬株式会社 会合制御によるポリペプチド製造方法
AU2006232920B2 (en) 2005-04-06 2011-09-29 Ibc Pharmaceuticals, Inc. Methods for generating stably linked complexes composed of homodimers, homotetramers or dimers of dimers and uses
US9296816B2 (en) 2005-04-15 2016-03-29 Macrogenics, Inc. Covalent diabodies and uses thereof
EP1896582A4 (en) 2005-05-09 2009-04-08 Ono Pharmaceutical Co HUMAN MONOCLONAL ANTIBODIES AGAINST PROGRAMMED CELL DEATH 1 (PD-1) AND METHOD FOR CREATING TREATMENT WITH ANTI-PD-1 ANTIBODIES ALONE OR IN COMBINATION WITH OTHER IMMUNOTHERAPEUTICS
NZ581779A (en) 2005-05-17 2011-09-30 Univ Connecticut Composition and methods for immunomodulation in an organism comprising interleukin-15 polypeptide and interleukin-15 receptor subunit A polypeptide complex
GB0510390D0 (en) 2005-05-20 2005-06-29 Novartis Ag Organic compounds
US20060263367A1 (en) 2005-05-23 2006-11-23 Fey Georg H Bispecific antibody devoid of Fc region and method of treatment using same
CN104356236B (zh) 2005-07-01 2020-07-03 E.R.施贵宝&圣斯有限责任公司 抗程序性死亡配体1(pd-l1)的人单克隆抗体
TW200726776A (en) 2005-07-29 2007-07-16 Friedrich Alexander University Of Erlangen Nuremberg CD33-specific single-chain immunotoxin and methods of use
US20070036773A1 (en) 2005-08-09 2007-02-15 City Of Hope Generation and application of universal T cells for B-ALL
US7612181B2 (en) 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
RU2515108C2 (ru) 2005-08-19 2014-05-10 Эббви Инк Иммуноглобулин с двойными вариабельными доменами и его применения
EP1757622B1 (en) 2005-08-26 2009-12-23 PLS Design GmbH Bivalent IgY antibody constructs for diagnostic and therapeutic applications
NZ608667A (en) 2005-10-07 2014-08-29 Exelixis Inc N-(3-amino-quinoxalin-2-yl)-sulfonamide derivatives and their use as phosphatidylinositol 3-kinase inhibitors
WO2007044887A2 (en) 2005-10-11 2007-04-19 Transtarget, Inc. Method for producing a population of homogenous tetravalent bispecific antibodies
US8623356B2 (en) 2005-11-29 2014-01-07 The University Of Sydney Demibodies: dimerization-activated therapeutic agents
EA016217B1 (ru) 2005-12-02 2012-03-30 Маунт Синай Скул Оф Медсин Химерные вирусы, представляющие неприродные поверхностные белки, и их применение
US9303080B2 (en) 2006-01-13 2016-04-05 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Codon optimized IL-15 and IL-15R-alpha genes for expression in mammalian cells
EP1981969A4 (en) 2006-01-19 2009-06-03 Genzyme Corp ANTI-GITRANT ANTIBODIES FOR THE TREATMENT OF CANCER
MX2008010561A (es) 2006-02-15 2009-03-02 Imclone Systems Inc Anticuerpos funcionales.
CA2646508A1 (en) 2006-03-17 2007-09-27 Biogen Idec Ma Inc. Stabilized polypeptide compositions
US8946391B2 (en) 2006-03-24 2015-02-03 The Regents Of The University Of California Construction of a multivalent scFv through alkyne-azide 1,3-dipolar cycloaddition
EP1999154B1 (en) 2006-03-24 2012-10-24 Merck Patent GmbH Engineered heterodimeric protein domains
EP4218801A3 (en) 2006-03-31 2023-08-23 Chugai Seiyaku Kabushiki Kaisha Antibody modification method for purifying bispecific antibody
EP2027153B1 (en) 2006-05-25 2014-04-30 Bayer Intellectual Property GmbH Dimeric molecular complexes
US20070274985A1 (en) 2006-05-26 2007-11-29 Stefan Dubel Antibody
CN105837690A (zh) 2006-06-12 2016-08-10 新兴产品开发西雅图有限公司 具有效应功能的单链多价结合蛋白
US8759297B2 (en) 2006-08-18 2014-06-24 Armagen Technologies, Inc. Genetically encoded multifunctional compositions bidirectionally transported between peripheral blood and the cns
WO2008027236A2 (en) 2006-08-30 2008-03-06 Genentech, Inc. Multispecific antibodies
US20100105136A1 (en) 2006-10-09 2010-04-29 The General Hospital Corporation Chimeric t-cell receptors and t-cells targeting egfrviii on tumors
DK3284825T3 (da) 2006-11-02 2021-05-25 Biomolecular Holdings Llc Fremgangsmåder til at fremstille hybride polypeptider med bevægelige dele
US20080131415A1 (en) 2006-11-30 2008-06-05 Riddell Stanley R Adoptive transfer of cd8 + t cell clones derived from central memory cells
WO2008140621A2 (en) 2006-12-21 2008-11-20 Mount Sinai School Of Medicine Of New York University Transgenic oncolytic viruses and uses thereof
CN101210048A (zh) 2006-12-29 2008-07-02 中国医学科学院血液学研究所 用于靶向结合髓系白血病细胞的抗cd33的工程抗体及其表达载体和用途
EP2139924B1 (en) 2007-03-29 2016-07-06 Genmab A/S Bispecific antibodies and methods for production thereof
PT2856876T (pt) 2007-03-30 2018-03-28 Memorial Sloan Kettering Cancer Center Expressão constitutiva de ligantes co-estimulatórios em linfócitos t adotivamente transferidos
US20080260738A1 (en) 2007-04-18 2008-10-23 Moore Margaret D Single chain fc, methods of making and methods of treatment
WO2008156712A1 (en) 2007-06-18 2008-12-24 N. V. Organon Antibodies to human programmed death receptor pd-1
NZ616254A (en) 2007-06-27 2015-04-24 Us Sec Dep Of Health And Human Services Complexes of il-15 and il-15ralpha and uses thereof
AU2008275589B2 (en) 2007-07-12 2013-11-21 Gitr, Inc. Combination therapies employing GITR binding molecules
CA2694488A1 (en) 2007-07-31 2009-02-05 Medimmune, Llc Multispecific epitope binding proteins and uses thereof
ES2628395T3 (es) 2007-08-15 2017-08-02 Bayer Pharma Aktiengesellschaft Anticuerpo regulado por proteasa
EP2212350B1 (en) 2007-10-26 2013-08-28 Governing Council of the University of Toronto Treating chronic viral infection by targetting TIM-3
MX2010005783A (es) 2007-11-27 2010-08-10 Ablynx Nv Secuencias de aminoacidos dirigidas contra citoquinas heterodimericas y/o sus receptores y polipeptidos que comprenden las mismas.
EA023031B1 (ru) 2007-11-30 2016-04-29 Глаксо Груп Лимитед Антиген-связывающая конструкция и ее применение
US8242247B2 (en) 2007-12-21 2012-08-14 Hoffmann-La Roche Inc. Bivalent, bispecific antibodies
US8227577B2 (en) 2007-12-21 2012-07-24 Hoffman-La Roche Inc. Bivalent, bispecific antibodies
US20090162359A1 (en) 2007-12-21 2009-06-25 Christian Klein Bivalent, bispecific antibodies
US9266967B2 (en) 2007-12-21 2016-02-23 Hoffmann-La Roche, Inc. Bivalent, bispecific antibodies
PT2235064E (pt) 2008-01-07 2016-03-01 Amgen Inc Método de preparação de moléculas heterodiméricas de fc de anticorpos utilizando efeitos de indução eletrostática
WO2009097140A1 (en) 2008-01-30 2009-08-06 Memorial Sloan-Kettering Cancer Center Methods for off -the -shelf tumor immunotherapy using allogeneic t-cell precursors
BRPI0907718A2 (pt) 2008-02-11 2017-06-13 Curetech Ltd método para tratar um tumor, método para melhorar a tolerabilidade a pelo menos um agente quimiterápico, método para aumentar a sobrevida de um indivíduo que tem um tumor, método para reduzir ou prevenir recidiva tumoral, uso de um anticorpo monoclonal humanizado ou seu fragmento e anticorpo monoclonal humanizado ou seu fragmento
MX2010009156A (es) 2008-02-21 2010-09-09 Astrazeneca Ab Terapia de combinacion 238.
US8379824B2 (en) 2008-03-06 2013-02-19 At&T Intellectual Property I, Lp Methods and apparatus to provide a network-based caller identification service in a voice over internet protocol network
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
CA2729810A1 (en) 2008-07-02 2010-01-07 Emergent Product Development Seattle, Llc Tgf-.beta. antagonist multi-target binding proteins
AR072999A1 (es) 2008-08-11 2010-10-06 Medarex Inc Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos
EP2328919A2 (en) 2008-08-25 2011-06-08 Amplimmune, Inc. Pd-i antagonists and methods for treating infectious disease
EP2350129B1 (en) 2008-08-25 2015-06-10 Amplimmune, Inc. Compositions of pd-1 antagonists and methods of use
JP2012501180A (ja) 2008-08-26 2012-01-19 シティ・オブ・ホープ Ｔ細胞の抗腫瘍エフェクター機能増進のための方法および組成物
US8586023B2 (en) 2008-09-12 2013-11-19 Mie University Cell capable of expressing exogenous GITR ligand
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
TW202442680A (zh) 2008-12-09 2024-11-01 美商建南德克公司 抗pd-l1抗體及其於增進t細胞功能之用途
EP2389443B1 (en) 2009-01-23 2018-11-14 Roger Williams Hospital Retroviral vectors encoding multiple highly homologous non-viral polypeptides and the use of same
EP2987856B1 (en) 2009-02-05 2018-07-25 Icahn School of Medicine at Mount Sinai Chimeric newcastle disease viruses and uses thereof
WO2010089411A2 (en) 2009-02-09 2010-08-12 Universite De La Mediterranee Pd-1 antibodies and pd-l1 antibodies and uses thereof
RU2506264C2 (ru) 2009-04-03 2014-02-10 Вэрастэм, Инк. Пиримидин-замещенные пуриновые соединения в качестве ингибиторов киназы (или киназ)
CA2759233C (en) 2009-04-27 2019-07-16 Oncomed Pharmaceuticals, Inc. Method for making heteromultimeric molecules
LT2990421T (lt) 2009-04-30 2018-04-25 Tel Hashomer Medical Research Infrastructure And Services Ltd. Anti-ceacam1 antikūnai ir jų panaudojimo būdai
CA2768965C (en) 2009-08-14 2019-06-04 George N. Pavlakis Use of il-15 to increase thymic output and to treat lymphopenia
IN2012DN01920A (cg-RX-API-DMAC7.html) 2009-09-03 2015-07-24 Schering Corp
DE102009045006A1 (de) * 2009-09-25 2011-04-14 Technische Universität Dresden Anti-CD33 Antikörper und ihre Anwendung zum Immunotargeting bei der Behandlung von CD33-assoziierten Erkrankungen
US8465743B2 (en) 2009-10-01 2013-06-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-vascular endothelial growth factor receptor-2 chimeric antigen receptors and use of same for the treatment of cancer
US9181527B2 (en) 2009-10-29 2015-11-10 The Trustees Of Dartmouth College T cell receptor-deficient T cell compositions
GB0919054D0 (en) 2009-10-30 2009-12-16 Isis Innovation Treatment of obesity
EP4049674A1 (en) 2009-11-03 2022-08-31 City of Hope Truncated epidermal growth factor receptor (egfrt) for transduced t cell selection
US8956828B2 (en) 2009-11-10 2015-02-17 Sangamo Biosciences, Inc. Targeted disruption of T cell receptor genes using engineered zinc finger protein nucleases
WO2011066342A2 (en) 2009-11-24 2011-06-03 Amplimmune, Inc. Simultaneous inhibition of pd-l1/pd-l2
WO2011090762A1 (en) 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Heterodimer binding proteins and uses thereof
EP2531216B1 (en) 2010-02-04 2019-03-27 The Trustees Of The University Of Pennsylvania Icos critically regulates the expansion and function of inflammatory human th17 cells
CA2796181C (en) 2010-04-20 2023-01-03 Genmab A/S Heterodimeric antibody fc-containing proteins and methods for production thereof
CA2802344C (en) 2010-06-18 2023-06-13 The Brigham And Women's Hospital, Inc. Bi-specific antibodies against tim-3 and pd-1 for immunotherapy in chronic immune conditions
US9011863B2 (en) 2010-07-09 2015-04-21 Exelixis, Inc. Combinations of kinase inhibitors for the treatment of cancer
EP2593450A1 (en) 2010-07-16 2013-05-22 Piramal Enterprises Limited Substituted imidazoquinoline derivatives as kinase inhibitors
US8945868B2 (en) 2010-07-21 2015-02-03 Sangamo Biosciences, Inc. Methods and compositions for modification of a HLA locus
MX349662B (es) * 2010-07-22 2017-08-08 Univ California Anticuerpos de antigenos antitumorales y metodos de uso.
AU2011319727B2 (en) 2010-10-27 2016-06-30 Baylor College Of Medicine Chimeric CD27 receptors for redirecting T cells to CD70-positive malignancies
WO2012074097A1 (ja) * 2010-12-03 2012-06-07 協和発酵キリン株式会社 抗ｃｄ３３抗体
PH12013501201A1 (en) 2010-12-09 2013-07-29 Univ Pennsylvania Use of chimeric antigen receptor-modified t cells to treat cancer
EP2651442B1 (en) 2010-12-14 2020-04-22 University of Maryland, Baltimore Universal anti-tag chimeric antigen receptor-expressing t cells and methods of treating cancer
US9402865B2 (en) 2011-01-18 2016-08-02 The Trustees Of The University Of Pennsylvania Compositions and methods for treating cancer
CN103561771B (zh) 2011-03-17 2019-01-04 伯明翰大学 重新定向的免疫治疗
BR112013024395B1 (pt) 2011-03-23 2021-10-26 Fred Hutchinson Cancer Research Center Composições adotivas de imunoterapia celular e método para fabricação da dita composição
WO2012127464A2 (en) 2011-03-23 2012-09-27 Gavish-Galilee Bio Applications Ltd Constitutively activated t cells for use in adoptive cell therapy
EP3323833B1 (en) 2011-04-01 2019-12-04 Memorial Sloan-Kettering Cancer Center T cell receptor-like bispecific antibodies specific for a wt1 peptide presented by hla-a2
ES2649967T3 (es) 2011-04-08 2018-01-16 Baylor College Of Medicine Inversión de los efectos del microentorno tumoral utilizando receptores quiméricos de citocinas
PT3459560T (pt) 2011-04-08 2021-05-24 Us Health Recetores de antigénio quimérico variante iii de recetor de fator de crescimento antiepidérmico e utilização dos mesmos para o tratamento de cancro
US20130071414A1 (en) 2011-04-27 2013-03-21 Gianpietro Dotti Engineered cd19-specific t lymphocytes that coexpress il-15 and an inducible caspase-9 based suicide gene for the treatment of b-cell malignancies
GB201108236D0 (en) * 2011-05-17 2011-06-29 Ucl Business Plc Method
US8841418B2 (en) 2011-07-01 2014-09-23 Cellerant Therapeutics, Inc. Antibodies that specifically bind to TIM3
EP2736539B1 (en) 2011-07-25 2017-08-23 Nationwide Children's Hospital, Inc. Recombinant virus products and methods for inhibition of expression of dux4
EA201490364A1 (ru) 2011-07-29 2014-08-29 Дзе Трастиз Оф Дзе Юниверсити Оф Пенсильвания Костимулирующие рецепторы-переключатели
SG2014009492A (en) 2011-08-11 2014-09-26 Intellikine Llc Kinase inhibitor polymorphs
US9833476B2 (en) 2011-08-31 2017-12-05 The Trustees Of Dartmouth College NKP30 receptor targeted therapeutics
WO2013039954A1 (en) 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies
AU2012308205A1 (en) 2011-09-16 2014-03-13 The Trustees Of The University Of Pennsylvania RNA engineered T cells for the treatment of cancer
WO2013040371A2 (en) 2011-09-16 2013-03-21 Baylor College Of Medicine Targeting the tumor microenvironment using manipulated nkt cells
KR101956751B1 (ko) 2011-10-07 2019-03-11 고쿠리츠다이가쿠호진 미에다이가쿠 키메라 항원 수용체
WO2013054320A1 (en) 2011-10-11 2013-04-18 Tel Hashomer Medical Research Infrastructure And Services Ltd. Antibodies to carcinoembryonic antigen-related cell adhesion molecule (ceacam)
RU2644243C2 (ru) 2011-10-20 2018-02-08 Дзе Юнайтед Стейтс Оф Америка, Эз Репрезентед Бай Дзе Секретари, Департмент Оф Хелс Энд Хьюман Сёрвисез Химерные антигенные рецепторы к cd22
WO2013060867A2 (en) 2011-10-27 2013-05-02 Genmab A/S Production of heterodimeric proteins
CA2892371C (en) 2011-12-01 2021-01-19 The Brigham And Women's Hospital, Inc. Anti-ceacam1 recombinant antibodies for cancer therapy
EP3594245A1 (en) 2012-02-13 2020-01-15 Seattle Children's Hospital d/b/a Seattle Children's Research Institute Bispecific chimeric antigen receptors and therapeutic uses thereof
SG11201404769UA (en) 2012-02-22 2014-11-27 Univ Pennsylvania Use of icos-based cars to enhance antitumor activity and car persistence
EP2817331B1 (en) 2012-02-22 2023-08-30 The Trustees of the University of Pennsylvania Use of the cd2 signaling domain in second-generation chimeric antigen receptors
SG11201404285VA (en) 2012-02-22 2014-10-30 Univ Pennsylvania Compositions and methods for generating a persisting population of t cells useful for the treatment of cancer
WO2013126726A1 (en) 2012-02-22 2013-08-29 The Trustees Of The University Of Pennsylvania Double transgenic t cells comprising a car and a tcr and their methods of use
US20130309223A1 (en) * 2012-05-18 2013-11-21 Seattle Genetics, Inc. CD33 Antibodies And Use Of Same To Treat Cancer
GB2537000C (en) 2012-05-25 2019-10-09 Univ California Methods and compositions for RNA-directed target DNA modification and for RNA-directed modulation of transcription
CN103483452B (zh) 2012-06-12 2021-08-13 上海细胞治疗集团有限公司 双信号独立的嵌合抗原受体及其用途
EP2872218A4 (en) 2012-07-13 2016-07-06 Univ Pennsylvania COMPOSITIONS AND METHOD FOR REGULATING HAIR GROWTH
EP2872617A4 (en) 2012-07-13 2015-12-09 Univ Pennsylvania EPITOP SPREADING IN CONNECTION WITH CAR T CELLS
MX2015000438A (es) 2012-07-13 2016-04-25 Univ Pennsylvania Manejo de toxicidad para actividad antitumoral de cars.
CN104884095A (zh) 2012-07-13 2015-09-02 宾夕法尼亚大学董事会 Cart19用于耗减正常b细胞以诱导耐受的用途
AU2013289979A1 (en) 2012-07-13 2015-01-22 The Trustees Of The University Of Pennsylvania Methods of assessing the suitability of transduced T cells for administration
KR20150029714A (ko) 2012-07-13 2015-03-18 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 이중특이적 항체의 공-도입에 의한 ｃａｒ 세포의 활성 증강
EP2879709B1 (en) 2012-07-31 2020-01-08 The Brigham and Women's Hospital, Inc. Modulation of the immune response
SMT202100005T1 (it) 2012-08-20 2021-05-07 Hutchinson Fred Cancer Res Metodo e composizioni per immunoterapia cellulare
US9937205B2 (en) 2012-09-04 2018-04-10 The Trustees Of The University Of Pennsylvania Inhibition of diacylglycerol kinase to augment adoptive T cell transfer
CN102952191B (zh) 2012-09-17 2014-05-14 浙江大学 全人源抗cd33单链抗体zjl101及其应用
AR092745A1 (es) 2012-10-01 2015-04-29 Univ Pennsylvania Composiciones que comprenden un dominio de union anti-fap y metodos para hacer blanco en celulas estromales para el tratamiento del cancer
EP2903637B1 (en) 2012-10-02 2019-06-12 Memorial Sloan-Kettering Cancer Center Compositions and methods for immunotherapy
US10117896B2 (en) 2012-10-05 2018-11-06 The Trustees Of The University Of Pennsylvania Use of a trans-signaling approach in chimeric antigen receptors
CN104853776B (zh) 2012-10-12 2021-04-09 布里格姆及妇女医院股份有限公司 免疫应答的增强
US20140186919A1 (en) 2012-12-12 2014-07-03 Feng Zhang Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation
KR20150105635A (ko) 2012-12-12 2015-09-17 더 브로드 인스티튜트, 인코퍼레이티드 서열 조작을 위한 crispr-cas 성분 시스템, 방법 및 조성물
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
US20160008399A1 (en) 2013-01-14 2016-01-14 Fred Hutchinson Cancer Research Center Compositions and methods for delivery of immune cells to treat un-resectable or non-resected tumor cells and tumor relapse
ES2760023T3 (es) 2013-02-20 2020-05-12 Univ Pennsylvania Tratamiento del cáncer utilizando receptor de antígeno quimérico anti-EGFRvIII humanizado
EP2958942B1 (en) 2013-02-20 2020-06-03 Novartis AG Effective targeting of primary human leukemia using anti-cd123 chimeric antigen receptor engineered t cells
EP3811954A1 (en) 2013-02-26 2021-04-28 Memorial Sloan Kettering Cancer Center Compositions and methods for immunotherapy
CN105339498A (zh) 2013-03-07 2016-02-17 贝勒医学院 癌症中靶向cd138
HK1220614A1 (zh) 2013-03-10 2017-05-12 Baylor College Of Medicine 耐化疗免疫细胞
CA2905272A1 (en) 2013-03-14 2014-10-02 Icahn School Of Medicine At Mount Sinai Newcastle disease viruses and uses thereof
EP2970426B1 (en) 2013-03-15 2019-08-28 Michael C. Milone Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
UY35468A (es) 2013-03-16 2014-10-31 Novartis Ag Tratamiento de cáncer utilizando un receptor quimérico de antígeno anti-cd19
WO2014165707A2 (en) 2013-04-03 2014-10-09 Memorial Sloan-Kettering Cancer Center Effective generation of tumor-targeted t-cells derived from pluripotent stem cells
EP2986636B1 (en) 2013-04-17 2018-11-14 Baylor College Of Medicine Immunosuppressive tgf-beta signal converter
US9629877B2 (en) 2013-05-14 2017-04-25 Board Of Regents, The University Of Texas System Human application of engineered chimeric antigen receptor (CAR) T-cells
SG11201509609SA (en) 2013-05-24 2015-12-30 Univ Texas Chimeric antigen receptor-targeting monoclonal antibodies
US20150140036A1 (en) 2013-11-13 2015-05-21 Novartis Institutes For Biomedical Research, Inc. Low, immune enhancing, dose mtor inhibitors and uses thereof
US9512084B2 (en) 2013-11-29 2016-12-06 Novartis Ag Amino pyrimidine derivatives
RU2714902C2 (ru) 2013-12-19 2020-02-20 Новартис Аг Химерные рецепторы антигена против мезотелина человека и их применение
EP4303229A3 (en) 2014-01-21 2024-04-17 Novartis AG Enhanced antigen presenting ability of car t cells by co-introduction of costimulatory molecules
KR102157924B1 (ko) * 2014-02-14 2020-10-26 셀렉티스 면역 세포들 및 병리 세포들 둘 다에 존재하는 항원을 타겟팅하기 위하여 조작된 면역치료용 세포들
JP2017513818A (ja) 2014-03-15 2017-06-01 ノバルティス アーゲー キメラ抗原受容体を使用する癌の処置
WO2015142661A1 (en) 2014-03-15 2015-09-24 Novartis Ag Regulatable chimeric antigen receptor
CA2944528C (en) * 2014-04-03 2021-08-10 Cellectis Cd33 specific chimeric antigen receptors for cancer immunotherapy
ES2876263T3 (es) 2014-04-07 2021-11-12 Novartis Ag Tratamiento del cáncer usando receptor de antígeno quimérico anti-cd19
EP3171882A1 (en) 2014-07-21 2017-05-31 Novartis AG Treatment of cancer using a cll-1 chimeric antigen receptor
SG11201700416TA (en) 2014-07-21 2017-02-27 Novartis Ag Treatment of cancer using a cd33 chimeric antigen receptor
US10174095B2 (en) 2014-07-21 2019-01-08 Novartis Ag Nucleic acid encoding a humanized anti-BCMA chimeric antigen receptor
US11542488B2 (en) 2014-07-21 2023-01-03 Novartis Ag Sortase synthesized chimeric antigen receptors
US20170274014A1 (en) 2014-07-21 2017-09-28 Jennifer Brogdon Combinations of low, immune enhancing, doses of mtor inhibitors and cars
EP3194585A1 (en) 2014-07-21 2017-07-26 Novartis AG Sortase molecules and uses thereof
EP3193915A1 (en) 2014-07-21 2017-07-26 Novartis AG Combinations of low, immune enhancing. doses of mtor inhibitors and cars
EP3174546B1 (en) 2014-07-31 2019-10-30 Novartis AG Subset-optimized chimeric antigen receptor-containing t-cells
AU2015301460B2 (en) 2014-08-14 2021-04-08 Novartis Ag Treatment of cancer using GFR alpha-4 chimeric antigen receptor
DK3183268T3 (da) 2014-08-19 2020-05-11 Univ Pennsylvania Behandling af cancer ved anvendelse af en cd123-kimær antigenreceptor
KR20210149228A (ko) 2014-09-17 2021-12-08 노파르티스 아게 입양 면역요법을 위한 키메라 수용체에 의한 세포독성 세포의 표적화
US10774388B2 (en) 2014-10-08 2020-09-15 Novartis Ag Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
WO2016061368A1 (en) 2014-10-15 2016-04-21 The Children's Hospital Of Philadelphia Compositions and methods for treating b-lymphoid malignancies
RU2751362C2 (ru) 2014-12-29 2021-07-13 Новартис Аг Способы получения экспрессирующих химерный антигенный рецептор клеток
US11459390B2 (en) 2015-01-16 2022-10-04 Novartis Ag Phosphoglycerate kinase 1 (PGK) promoters and methods of use for expressing chimeric antigen receptor
WO2016126608A1 (en) 2015-02-02 2016-08-11 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
US20180140602A1 (en) 2015-04-07 2018-05-24 Novartis Ag Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives
HUE059218T2 (hu) 2015-04-08 2022-11-28 Novartis Ag CD20-terápiák, CD22-terápiák és kombinációs terápiák CD19 kiméra antigénreceptort (CAR-t) expresszáló sejttel
US11896614B2 (en) 2015-04-17 2024-02-13 Novartis Ag Methods for improving the efficacy and expansion of chimeric antigen receptor-expressing cells
EP3286211A1 (en) 2015-04-23 2018-02-28 Novartis AG Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
SG10201912978PA (en) 2015-07-21 2020-02-27 Novartis Ag Methods for improving the efficacy and expansion of immune cells
WO2017027392A1 (en) 2015-08-07 2017-02-16 Novartis Ag Treatment of cancer using chimeric cd3 receptor proteins
CN108780084B (zh) 2015-09-03 2022-07-22 诺华股份有限公司 预测细胞因子释放综合征的生物标志物
EP3350320A1 (en) 2015-09-17 2018-07-25 Novartis AG Car t cell therapies with enhanced efficacy
EP4643874A2 (en) 2015-12-22 2025-11-05 Novartis AG Mesothelin chimeric antigen receptor (car) and antibody against pd-l1 inhibitor for combined use in anticancer therapy
EP4219689A3 (en) 2015-12-30 2023-12-20 Novartis AG Immune effector cell therapies with enhanced efficacy
US20190336504A1 (en) 2016-07-15 2019-11-07 Novartis Ag Treatment and prevention of cytokine release syndrome using a chimeric antigen receptor in combination with a kinase inhibitor
CN110214150A (zh) 2016-07-28 2019-09-06 诺华股份有限公司 嵌合抗原受体和pd-1抑制剂的组合疗法
JP2019527696A (ja) 2016-08-01 2019-10-03 ノバルティス アーゲー プロｍ２マクロファージ分子の阻害剤と組み合わせてキメラ抗原受容体を用いる癌の処置
EP3523290A4 (en) 2016-09-30 2020-07-29 Novartis AG IMPROVED EFFICIENCY IMMUNE EFFICIENT CELL THERAPIES
CA3039646A1 (en) 2016-10-07 2018-04-12 Novartis Ag Chimeric antigen receptors for the treatment of cancer
EP3574005B1 (en) 2017-01-26 2021-12-15 Novartis AG Cd28 compositions and methods for chimeric antigen receptor therapy
CN110582509A (zh) 2017-01-31 2019-12-17 诺华股份有限公司 使用具有多特异性的嵌合t细胞受体蛋白治疗癌症
EP3589647A1 (en) 2017-02-28 2020-01-08 Novartis AG Shp inhibitor compositions and uses for chimeric antigen receptor therapy
KR20190127892A (ko) 2017-03-22 2019-11-13 노파르티스 아게 바이오마커 및 효능이 증진된 car t 세포 요법
EP3615055A1 (en) 2017-04-28 2020-03-04 Novartis AG Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
CA3079407A1 (en) 2017-10-18 2019-04-25 Novartis Ag Compositions and methods for selective protein degradation
US20200061113A1 (en) 2018-04-12 2020-02-27 Novartis Ag Chimeric antigen receptor therapy characterization assays and uses thereof
US20200085869A1 (en) 2018-05-16 2020-03-19 Novartis Ag Therapeutic regimens for chimeric antigen receptor therapies
MY208825A (en) 2018-06-13 2025-05-30 Novartis Ag Bcma chimeric antigen receptors and uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015090229A1 (en) * 2013-12-20 2015-06-25 Novartis Ag Regulatable chimeric antigen receptor

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
C. O'HEAR ET AL: "Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia", HAEMATOLOGICA, THE HEMATOLOGY JOURNAL : OFFICIAL ORGAN OF THE EUROPEAN HEMATOLOGY ASSOCIATION, vol. 100, no. 3, 5 December 2014 (2014-12-05), IT, pages 336 - 344, XP055227759, ISSN: 0390-6078, DOI: 10.3324/haematol.2014.112748 *
CAROL E O'HEAR ET AL: "Anti-CD33 Chimeric Antigen Receptor Therapy For Acute Myeloid Leukemia", INTERNET CITATION, 1 November 2013 (2013-11-01), pages 1441, XP002727865, ISSN: 0006-4971, Retrieved from the Internet <URL:https://ash.confex.com/ash/2013/webprogram/Paper65623.html> [retrieved on 20140822] *
PIZZITOLA I ET AL: "Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo", LEUKEMIA, MACMILLAN PRESS LTD, US, vol. 28, no. 8, 21 February 2014 (2014-02-21), pages 1596 - 1605, XP002727950, ISSN: 0887-6924, [retrieved on 20140207] *
QUAN-SHUN WANG ET AL: "Treatment of CD33-directed Chimeric Antigen Receptor-modified T Cells in One Patient With Relapsed and Refractory Acute Myeloid Leukemia", MOLECULAR THERAPY, vol. 23, no. 1, 23 September 2014 (2014-09-23), pages 184 - 191, XP055191799, ISSN: 1525-0016, DOI: 10.1038/mt.2014.164 *
SADELAIN M ET AL: "The promise and potential pitfalls of chimeric antigen receptors", CURRENT OPINION IN IMMUNOLOGY, ELSEVIER, OXFORD, GB, vol. 21, no. 2, 1 April 2009 (2009-04-01), pages 215 - 223, XP026058399, ISSN: 0952-7915, [retrieved on 20090325], DOI: 10.1016/J.COI.2009.02.009 *

Cited By (213)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11865167B2 (en) 2013-02-20 2024-01-09 Novartis Ag Treatment of cancer using humanized anti-EGFRvIII chimeric antigen receptor
US10308717B2 (en) 2013-02-20 2019-06-04 Novartis Ag Treatment of cancer using humanized anti-EGFRvIII chimeric antigen receptor
US11028177B2 (en) 2013-02-20 2021-06-08 Novartis Ag Effective targeting of primary human leukemia using anti-CD123 chimeric antigen receptor engineered T cells
US9745368B2 (en) 2013-03-15 2017-08-29 The Trustees Of The University Of Pennsylvania Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
US11919946B2 (en) 2013-03-15 2024-03-05 Novartis Ag Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
US10640553B2 (en) 2013-03-15 2020-05-05 Novartis Ag Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
US10221245B2 (en) 2013-03-16 2019-03-05 Novartis Ag Treatment of cancer using humanized anti-CD19 chimeric antigen receptor
US10927184B2 (en) 2013-03-16 2021-02-23 Novartis Ag Treatment of cancer using humanized anti-CD19 chimeric antigen receptor
US11999794B2 (en) 2013-12-19 2024-06-04 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
US10640569B2 (en) 2013-12-19 2020-05-05 Novartis Ag Human mesothelin chimeric antigen receptors and uses thereof
US10287354B2 (en) 2013-12-20 2019-05-14 Novartis Ag Regulatable chimeric antigen receptor
US11578130B2 (en) 2013-12-20 2023-02-14 Novartis Ag Regulatable chimeric antigen receptor
US12162922B2 (en) 2014-01-21 2024-12-10 Novartis Ag Enhanced antigen presenting ability of RNA car T cells by co-introduction of costimulatory molecules
US11028143B2 (en) 2014-01-21 2021-06-08 Novartis Ag Enhanced antigen presenting ability of RNA CAR T cells by co-introduction of costimulatory molecules
US10357514B2 (en) 2014-04-07 2019-07-23 The Trustees Of The University Of Pennsylvania Treatment of cancer using anti-CD19 Chimeric Antigen Receptor
US9777061B2 (en) 2014-07-21 2017-10-03 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
US12338287B2 (en) 2014-07-21 2025-06-24 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
US10174095B2 (en) 2014-07-21 2019-01-08 Novartis Ag Nucleic acid encoding a humanized anti-BCMA chimeric antigen receptor
US10568947B2 (en) 2014-07-21 2020-02-25 Novartis Ag Treatment of cancer using a CLL-1 chimeric antigen receptor
US12214037B2 (en) 2014-07-21 2025-02-04 Novartis Ag Treatment of cancer using humanized anti-BCMA chimeric antigen receptor
US11542488B2 (en) 2014-07-21 2023-01-03 Novartis Ag Sortase synthesized chimeric antigen receptors
US10851166B2 (en) 2014-07-21 2020-12-01 Novartis Ag Treatment of cancer using a CD33 chimeric antigen receptor
US11084880B2 (en) 2014-07-21 2021-08-10 Novartis Ag Anti-BCMA chimeric antigen receptor
US10703819B2 (en) 2014-08-09 2020-07-07 The Trustees Of The University Of Pennsylvania Treatment of cancer using a CD123 chimeric antigen receptor
US11591404B2 (en) 2014-08-19 2023-02-28 Novartis Ag Treatment of cancer using a CD123 chimeric antigen receptor
US9815901B2 (en) 2014-08-19 2017-11-14 Novartis Ag Treatment of cancer using a CD123 chimeric antigen receptor
US10577417B2 (en) 2014-09-17 2020-03-03 Novartis Ag Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
US11981731B2 (en) 2014-09-17 2024-05-14 The Trustees Of The University Of Pennsylvania Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
US10774388B2 (en) 2014-10-08 2020-09-15 Novartis Ag Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
US10273300B2 (en) 2014-12-29 2019-04-30 The Trustees Of The University Of Pennsylvania Methods of making chimeric antigen receptor-expressing cells
US11459390B2 (en) 2015-01-16 2022-10-04 Novartis Ag Phosphoglycerate kinase 1 (PGK) promoters and methods of use for expressing chimeric antigen receptor
US11161907B2 (en) 2015-02-02 2021-11-02 Novartis Ag Car-expressing cells against multiple tumor antigens and uses thereof
US12012443B2 (en) 2015-03-05 2024-06-18 Fred Hutchinson Cancer Center Immunomodulatory fusion proteins and uses thereof
US12344657B2 (en) 2015-04-08 2025-07-01 Novartis Ag CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell
US11149076B2 (en) 2015-04-08 2021-10-19 Novartis Ag CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell
US10253086B2 (en) 2015-04-08 2019-04-09 Novartis Ag CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell
US11896614B2 (en) 2015-04-17 2024-02-13 Novartis Ag Methods for improving the efficacy and expansion of chimeric antigen receptor-expressing cells
US12128069B2 (en) 2015-04-23 2024-10-29 The Trustees Of The University Of Pennsylvania Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
US12240884B2 (en) 2015-07-21 2025-03-04 Novartis Ag Methods for improving the efficacy and expansion of immune cells
WO2017015427A1 (en) 2015-07-21 2017-01-26 Novartis Ag Methods for improving the efficacy and expansion of immune cells
US10829735B2 (en) 2015-07-21 2020-11-10 The Trustees Of The University Of Pennsylvania Methods for improving the efficacy and expansion of immune cells
US11667691B2 (en) 2015-08-07 2023-06-06 Novartis Ag Treatment of cancer using chimeric CD3 receptor proteins
US11747346B2 (en) 2015-09-03 2023-09-05 Novartis Ag Biomarkers predictive of cytokine release syndrome
WO2017040930A2 (en) 2015-09-03 2017-03-09 The Trustees Of The University Of Pennsylvania Biomarkers predictive of cytokine release syndrome
US10786535B2 (en) 2015-10-16 2020-09-29 The Trustees Of Columbia University In The City Of New York Compositions and methods for inhibition of lineage specific antigens
US10668103B2 (en) 2015-10-16 2020-06-02 The Trustees Of Columbia University In The City Of New York Compositions and methods for inhibition of lineage specific antigens
US10660919B2 (en) 2015-10-16 2020-05-26 The Trustees Of Columbia University In The City Of New York Compositions and methods for inhibition of lineage specific antigens
US10912799B2 (en) 2015-10-16 2021-02-09 The Trustees Of Columbia University In The City Of New York Compositions and methods for inhibition of lineage specific antigens
US11242377B2 (en) 2015-10-23 2022-02-08 Autolus Limited Chimeric receptor with ligand binding exodomain and cytokine and T cell signalling endodomains
AU2016342560B2 (en) * 2015-10-23 2021-03-04 Autolus Limited Receptor
US12037583B2 (en) 2015-12-04 2024-07-16 Novartis Ag Compositions and methods for immunooncology
US11413340B2 (en) 2015-12-22 2022-08-16 Novartis Ag Mesothelin chimeric antigen receptor (CAR) and antibody against PD-L1 inhibitor for combined use in anticancer therapy
US12186278B2 (en) 2015-12-22 2025-01-07 Novartis Ag Mesothelin chimeric antigen receptor (CAR) and antibody against PD-L1 inhibitor for combined use in anticancer therapy
EP4477748A2 (en) 2015-12-28 2024-12-18 Novartis AG Methods of making chimeric antigen receptor-expressing cells
WO2017114497A1 (en) 2015-12-30 2017-07-06 Novartis Ag Immune effector cell therapies with enhanced efficacy
EP4219689A2 (en) 2015-12-30 2023-08-02 Novartis AG Immune effector cell therapies with enhanced efficacy
EP3413045A4 (en) * 2016-02-09 2019-09-18 Japanese Foundation For Cancer Research DIAGNOSTIC MARKER FOR RARE HEMATOPOETIC TUMOR, TEST METHOD, THERAPEUTIC AGENT AND SCREENING METHOD
WO2017149515A1 (en) 2016-03-04 2017-09-08 Novartis Ag Cells expressing multiple chimeric antigen receptor (car) molecules and uses therefore
US11834511B2 (en) 2016-03-18 2023-12-05 Fred Hutchinson Cancer Center Compositions and methods for CD20 immunotherapy
JP7065782B2 (ja) 2016-03-18 2022-05-12 フレッド ハッチンソン キャンサー リサーチ センター Ｃｄ２０免疫療法のための組成物および方法
JP7397840B2 (ja) 2016-03-18 2023-12-13 フレッド ハッチンソン キャンサー センター Ｃｄ２０免疫療法のための組成物および方法
JP2019515652A (ja) * 2016-03-18 2019-06-13 フレッド ハッチンソン キャンサー リサーチ センター Ｃｄ２０免疫療法のための組成物および方法
JP2022002550A (ja) * 2016-03-18 2022-01-11 フレッド ハッチンソン キャンサー リサーチ センター Ｃｄ２０免疫療法のための組成物および方法
US11549099B2 (en) 2016-03-23 2023-01-10 Novartis Ag Cell secreted minibodies and uses thereof
WO2017165683A1 (en) 2016-03-23 2017-09-28 Novartis Ag Cell secreted minibodies and uses thereof
US11446398B2 (en) 2016-04-11 2022-09-20 Obsidian Therapeutics, Inc. Regulated biocircuit systems
CN109311963A (zh) * 2016-04-14 2019-02-05 蓝鸟生物公司 救助嵌合抗原受体系统
US11976116B2 (en) 2016-04-14 2024-05-07 2Seventy Bio, Inc. Salvage chimeric antigen receptor systems
EP3443002A4 (en) * 2016-04-14 2019-12-04 Bluebird Bio, Inc. SYSTEMS FOR RECOVERED CHIMERIC ANTIGEN RECEPTORS
EP4219721A2 (en) 2016-04-15 2023-08-02 Novartis AG Compositions and methods for selective protein expression
WO2017181119A2 (en) 2016-04-15 2017-10-19 Novartis Ag Compositions and methods for selective protein expression
US11787848B2 (en) 2016-06-08 2023-10-17 Precigen, Inc. CD33 specific chimeric antigen receptors
JP7591342B2 (ja) 2016-06-08 2024-11-28 プレシゲン，インコーポレイテッド Ｃｄ３３特異的キメラ抗原受容体
US11180553B2 (en) 2016-06-16 2021-11-23 Autolus Limited Chimeric antigen receptor
WO2018013918A2 (en) 2016-07-15 2018-01-18 Novartis Ag Treatment and prevention of cytokine release syndrome using a chimeric antigen receptor in combination with a kinase inhibitor
WO2018016656A1 (ja) * 2016-07-20 2018-01-25 一般社団法人 東京血液疾患研究所 骨髄異形成症候群の診断方法
JPWO2018016656A1 (ja) * 2016-07-20 2019-09-05 一般社団法人東京血液疾患研究所 骨髄異形成症候群の診断方法
CN110035768A (zh) * 2016-07-26 2019-07-19 泰莎治疗私人有限公司 嵌合抗原受体
WO2018023025A1 (en) 2016-07-28 2018-02-01 Novartis Ag Combination therapies of chimeric antigen receptors adn pd-1 inhibitors
WO2018026819A2 (en) 2016-08-01 2018-02-08 Novartis Ag Treatment of cancer using a chimeric antigen receptor in combination with an inhibitor of a pro-m2 macrophage molecule
WO2018064387A1 (en) 2016-09-28 2018-04-05 Novartis Ag Porous membrane-based macromolecule delivery system
US11026976B2 (en) 2016-10-07 2021-06-08 Novartis Ag Nucleic acid molecules encoding chimeric antigen receptors comprising a CD20 binding domain
US11872249B2 (en) 2016-10-07 2024-01-16 Novartis Ag Method of treating cancer by administering immune effector cells expressing a chimeric antigen receptor comprising a CD20 binding domain
US10525083B2 (en) 2016-10-07 2020-01-07 Novartis Ag Nucleic acid molecules encoding chimeric antigen receptors comprising a CD20 binding domain
USRE49847E1 (en) 2016-10-07 2024-02-27 Novartis Ag Nucleic acid molecules encoding chimeric antigen receptors comprising a CD20 binding domain
US12269859B2 (en) 2016-12-02 2025-04-08 Angeles Therapeutics, Inc. Synthetic immune receptors and methods of use thereof
EP3570850A4 (en) * 2017-01-18 2020-10-14 Thalia Papayannopoulou PACKAGING COMPOSITIONS AND METHODS FOR A TRANSPLANT RECEIVER
EP4043485A1 (en) 2017-01-26 2022-08-17 Novartis AG Cd28 compositions and methods for chimeric antigen receptor therapy
US11535662B2 (en) 2017-01-26 2022-12-27 Novartis Ag CD28 compositions and methods for chimeric antigen receptor therapy
EP4194473A1 (en) * 2017-02-08 2023-06-14 Cellular Biomedicine Group Inc. Construction of chimeric antigen receptor targeting cd20 antigen and activity identification of engineered t cells thereof
US11975029B2 (en) 2017-02-28 2024-05-07 Vor Biopharma Inc. Compositions and methods for inhibition of lineage specific proteins
US12365906B2 (en) 2017-03-17 2025-07-22 Fred Hutchinson Cancer Center Immunomodulatory fusion proteins and uses thereof
US11725210B2 (en) 2017-03-17 2023-08-15 Fred Hutchinson Cancer Center Immunomodulatory fusion proteins and uses thereof
US11851659B2 (en) 2017-03-22 2023-12-26 Novartis Ag Compositions and methods for immunooncology
JP7448896B2 (ja) 2017-03-24 2024-03-13 レンティジェン・テクノロジー・インコーポレイテッド 抗ｃｄ３３免疫療法によりがんを処置するための組成物および方法
US11464801B2 (en) 2017-03-24 2022-10-11 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD33 immunotherapy
US10426797B2 (en) 2017-03-24 2019-10-01 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD33 immunotherapy
JP2022180404A (ja) * 2017-03-24 2022-12-06 レンティジェン・テクノロジー・インコーポレイテッド 抗ｃｄ３３免疫療法によりがんを処置するための組成物および方法
CN112695050A (zh) * 2017-03-24 2021-04-23 莱蒂恩技术公司 用于用抗cd33免疫疗法治疗癌症的组合物和方法
CN110997719A (zh) * 2017-03-24 2020-04-10 莱蒂恩技术公司 用于用抗cd33免疫疗法治疗癌症的组合物和方法
JP2020513829A (ja) * 2017-03-24 2020-05-21 レンティジェン・テクノロジー・インコーポレイテッドＬｅｎｔｉｇｅｎ Ｔｅｃｈｎｏｌｏｇｙ， Ｉｎｃ． 抗ｃｄ３３免疫療法によりがんを処置するための組成物および方法
WO2018175988A1 (en) * 2017-03-24 2018-09-27 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-cd33 immunotherapy
JP2024073443A (ja) * 2017-03-24 2024-05-29 レンティジェン・テクノロジー・インコーポレイテッド 抗ｃｄ３３免疫療法によりがんを処置するための組成物および方法
AU2018240556B2 (en) * 2017-03-24 2025-02-27 Lentigen Technology, Inc. Compositions and methods for treating cancer with anti-CD33 immunotherapy
JP7137896B2 (ja) 2017-03-24 2022-09-15 レンティジェン・テクノロジー・インコーポレイテッド 抗ｃｄ３３免疫療法によりがんを処置するための組成物および方法
CN110612109A (zh) * 2017-04-28 2019-12-24 锕医药有限责任公司 使用BCL-2抑制剂连同α-发射放射免疫治疗来治疗癌症的方法
CN107353343A (zh) * 2017-07-04 2017-11-17 武汉波睿达生物科技有限公司 一种靶向表达cd33表面抗原的细胞的嵌合抗原受体
CN107267619A (zh) * 2017-07-04 2017-10-20 武汉波睿达生物科技有限公司 一种检测靶向cd33的cart细胞中car表达的荧光定量试剂盒
JP2020530768A (ja) * 2017-07-20 2020-10-29 エイチ リー モフィット キャンサー センター アンド リサーチ インスティテュート インコーポレイテッド Ｃｄ３３発現がんを標的とするための組成物および方法
US11479606B2 (en) 2017-07-20 2022-10-25 H. Lee Moffitt Cancer Center And Research Institute, Inc. Compositions and methods for targeting CD33-expressing cancers
US12037394B2 (en) 2017-07-20 2024-07-16 H. Lee Moffitt Cancer Center And Research Institute, Inc. Compositions and methods for targeting CD33-expressing cancers
JP7252651B2 (ja) 2017-07-20 2023-04-05 エイチ リー モフィット キャンサー センター アンド リサーチ インスティテュート インコーポレイテッド Ｃｄ３３発現がんを標的とするための組成物および方法
WO2019079569A1 (en) 2017-10-18 2019-04-25 Novartis Ag COMPOSITIONS AND METHODS FOR SELECTIVE DEGRADATION OF A PROTEIN
US11999802B2 (en) 2017-10-18 2024-06-04 Novartis Ag Compositions and methods for selective protein degradation
WO2019084288A1 (en) 2017-10-25 2019-05-02 Novartis Ag METHODS FOR DESIGNING CHIMERIC ANTIGENIC RECEPTOR EXPRESSION CELLS
US11732040B2 (en) * 2017-11-27 2023-08-22 Bivictrix Limited Anti-CD33 and anti-CD7 combination treatment
EP4628503A3 (en) * 2017-12-15 2025-12-17 Autolus Limited Cell
US12304942B2 (en) 2017-12-15 2025-05-20 Autolus Limited Cell comprising a chimeric antigen receptor or a transgenic T-cell receptor and comprising a chimeric TNF receptor
WO2019116046A1 (en) * 2017-12-15 2019-06-20 Autolus Limited Cell
US12258381B2 (en) 2018-02-09 2025-03-25 National University Of Singapore Activating chimeric receptors and uses thereof in natural killer cell immunotherapy
WO2019154313A1 (zh) 2018-02-11 2019-08-15 江苏恒瑞医药股份有限公司 一种分离的嵌合抗原受体以及包含其的修饰t细胞及用途
US12403178B2 (en) 2018-03-12 2025-09-02 Immunitybio, Inc. Use of CD33CAR modified high affinity NK cells (t-haNK) to reduce myeloid-derived suppressor cells suppressor activity (or reduce negative impact on NK cell activity)
CN112004829A (zh) * 2018-03-12 2020-11-27 南克维斯特公司 Cd33car修饰的高亲和力nk细胞(t-hank)用于降低髓系衍生的抑制细胞的抑制活性(或降低对nk细胞活性的负面影响)的用途
WO2019177986A1 (en) * 2018-03-12 2019-09-19 Nantkwest, Inc. Use of cd33car modified high affinity nk cells (t-hank) to reduce myeloid-derived suppressor cells suppressor activity (or reduce negative impact on nk cell activity)
US11813292B2 (en) 2018-03-12 2023-11-14 Immunity Bio, Inc. Use of CD33CAR modified high affinity NK cells (t-haNK) to reduce myeloid-derived suppressor cells suppressor activity (or reduce negative impact on NK cell activity)
WO2019178382A1 (en) * 2018-03-14 2019-09-19 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-cd33 chimeric antigen receptors and their uses
US12441787B2 (en) 2018-04-02 2025-10-14 National University Of Singapore Neutralization of human cytokines with membrane-bound anti-cytokine non-signaling binders expressed in immune cells
WO2019210153A1 (en) 2018-04-27 2019-10-31 Novartis Ag Car t cell therapies with enhanced efficacy
WO2019213282A1 (en) 2018-05-01 2019-11-07 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
WO2019227003A1 (en) 2018-05-25 2019-11-28 Novartis Ag Combination therapy with chimeric antigen receptor (car) therapies
WO2019237035A1 (en) 2018-06-08 2019-12-12 Intellia Therapeutics, Inc. Compositions and methods for immunooncology
WO2019241315A1 (en) 2018-06-12 2019-12-19 Obsidian Therapeutics, Inc. Pde5 derived regulatory constructs and methods of use in immunotherapy
US11608382B2 (en) 2018-06-13 2023-03-21 Novartis Ag BCMA chimeric antigen receptors and uses thereof
US11939389B2 (en) 2018-06-13 2024-03-26 Novartis Ag BCMA chimeric antigen receptors and uses thereof
US11952428B2 (en) 2018-06-13 2024-04-09 Novartis Ag BCMA chimeric antigen receptors and uses thereof
WO2020012337A1 (en) 2018-07-10 2020-01-16 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and their use in the treatment of i karos family zinc finger 2 (ikzf2)-dependent diseases
US11389485B2 (en) 2018-08-28 2022-07-19 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
US12251403B2 (en) 2018-08-28 2025-03-18 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
US10925902B2 (en) 2018-08-28 2021-02-23 Vor Biopharma, Inc Genetically engineered hematopoietic stem cells and uses thereof
US11382932B2 (en) 2018-08-28 2022-07-12 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
US11903973B2 (en) 2018-08-28 2024-02-20 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
US11464807B2 (en) 2018-08-28 2022-10-11 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
US11571445B2 (en) 2018-08-28 2023-02-07 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
US11559551B2 (en) 2018-08-28 2023-01-24 Vor Biopharma Inc. Genetically engineered hematopoietic stem cells and uses thereof
WO2020047452A2 (en) 2018-08-31 2020-03-05 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
WO2020047449A2 (en) 2018-08-31 2020-03-05 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
US12097219B2 (en) 2018-09-10 2024-09-24 Legend Biotech Ireland Limited Single-domain antibodies against CLL1 and constructs thereof
EP3850011A4 (en) * 2018-09-10 2022-10-19 Nanjing Legend Biotech Co., Ltd. Single-domain antibodies against cd33 and constructs thereof
US12275788B2 (en) 2018-09-10 2025-04-15 Legend Biotech Ireland Limited Single-domain antibodies against CD33 and constructs thereof
US12398402B2 (en) 2018-09-12 2025-08-26 Fred Hutchinson Cancer Center Reducing CD33 expression to selectively protect therapeutic cells
WO2020056170A1 (en) * 2018-09-12 2020-03-19 Fred Hutchinson Cancer Research Center Reducing cd33 expression to selectively protect therapeutic cells
WO2020086742A1 (en) 2018-10-24 2020-04-30 Obsidian Therapeutics, Inc. Er tunable protein regulation
US12257286B2 (en) 2018-10-31 2025-03-25 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
US12264189B2 (en) 2018-10-31 2025-04-01 Mayo Foundation For Medical Education And Research Methods and materials for treating cancer
WO2020095107A1 (en) * 2018-11-07 2020-05-14 Crispr Therapeutics Ag Anti-cd33 immune cell cancer therapy
US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof
WO2020123716A1 (en) 2018-12-11 2020-06-18 Obsidian Therapeutics, Inc. Membrane bound il12 compositions and methods for tunable regulation
US12291560B2 (en) 2018-12-14 2025-05-06 Regeneron Pharmaceuticals, Inc. Dimerizing agent regulated immunoreceptor complexes
WO2020128972A1 (en) 2018-12-20 2020-06-25 Novartis Ag Dosing regimen and pharmaceutical combination comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2020165834A1 (en) 2019-02-15 2020-08-20 Novartis Ag Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020165833A1 (en) 2019-02-15 2020-08-20 Novartis Ag 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2020176397A1 (en) 2019-02-25 2020-09-03 Novartis Ag Mesoporous silica particles compositions for viral delivery
US12398187B2 (en) 2019-03-05 2025-08-26 Nkarta, Inc. CD19-directed chimeric antigen receptors and uses thereof in immunotherapy
WO2020185632A1 (en) 2019-03-08 2020-09-17 Obsidian Therapeutics, Inc. Human carbonic anhydrase 2 compositions and methods for tunable regulation
WO2020210678A1 (en) 2019-04-12 2020-10-15 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
WO2020219742A1 (en) 2019-04-24 2020-10-29 Novartis Ag Compositions and methods for selective protein degradation
US12084502B2 (en) 2019-05-04 2024-09-10 Inhibrx Biosciences, Inc. CD33-binding polypeptides and uses thereof
CN114206928B (zh) * 2019-05-08 2025-08-08 印希彼生物科学公司 Cd33靶向免疫疗法
EP3966251A4 (en) * 2019-05-08 2023-05-10 Inhibrx, Inc. IMMUNOTHERAPIES TARGETED AGAINST CD33
CN114206928A (zh) * 2019-05-08 2022-03-18 印希彼有限公司 Cd33靶向免疫疗法
WO2020252405A1 (en) 2019-06-12 2020-12-17 Obsidian Therapeutics, Inc. Ca2 compositions and methods for tunable regulation
WO2020252404A1 (en) 2019-06-12 2020-12-17 Obsidian Therapeutics, Inc. Ca2 compositions and methods for tunable regulation
EP3999082A4 (en) * 2019-07-17 2022-11-30 National University of Singapore Functional binders synthesized and secreted by immune cells
WO2021046451A1 (en) 2019-09-06 2021-03-11 Obsidian Therapeutics, Inc. Compositions and methods for dhfr tunable protein regulation
US12383581B2 (en) 2019-10-11 2025-08-12 The Trustees Of The University Of Pennsylvania Compositions and methods for targeting CD13 and TIM-3 with CAR T cells to treat acute myeloid leukemia
US12509455B2 (en) 2019-11-07 2025-12-30 Dana-Farber Cancer Institute, Inc. Imidazopyridine derivatives and aza-imidazopyridine derivatives as Janus kinase 2 inhibitors and uses thereof
US11975026B2 (en) 2019-11-26 2024-05-07 Novartis Ag CD19 and CD22 chimeric antigen receptors and uses thereof
WO2021108661A2 (en) 2019-11-26 2021-06-03 Novartis Ag Chimeric antigen receptors and uses thereof
US12383601B2 (en) 2019-11-26 2025-08-12 Novartis Ag Chimeric antigen receptors and uses thereof
US12344651B2 (en) 2019-11-26 2025-07-01 Novartis Ag CD19 and CD22 chimeric antigen receptors and uses thereof
WO2021123996A1 (en) 2019-12-20 2021-06-24 Novartis Ag Uses of anti-tgf-beta antibodies and checkpoint inhibitors for the treatment of proliferative diseases
WO2021173985A2 (en) 2020-02-27 2021-09-02 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
WO2021173995A2 (en) 2020-02-27 2021-09-02 Novartis Ag Methods of making chimeric antigen receptor-expressing cells
US12448432B2 (en) 2020-03-17 2025-10-21 AbelZeta Inc. Combined chimeric antigen receptor targeting CD19 and CD20 and application thereof
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12275717B2 (en) 2020-05-06 2025-04-15 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
WO2021252920A1 (en) 2020-06-11 2021-12-16 Novartis Ag Zbtb32 inhibitors and uses thereof
WO2021260528A1 (en) 2020-06-23 2021-12-30 Novartis Ag Dosing regimen comprising 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives
WO2022029573A1 (en) 2020-08-03 2022-02-10 Novartis Ag Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
WO2022035794A1 (en) * 2020-08-13 2022-02-17 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Igg4 hinge-containing chimeric antigen receptors targeting glypican-1 (gpc1) for treating solid tumors
WO2022040586A2 (en) 2020-08-21 2022-02-24 Novartis Ag Compositions and methods for in vivo generation of car expressing cells
JP2023541456A (ja) * 2020-09-14 2023-10-02 ブイオーアール バイオファーマ インコーポレーテッド がん治療用キメラ抗原受容体
WO2022056490A1 (en) * 2020-09-14 2022-03-17 Vor Biopharma, Inc. Chimeric antigen receptors for treatment of cancer
US11883432B2 (en) 2020-12-18 2024-01-30 Century Therapeutics, Inc. Chimeric antigen receptor system with adaptable receptor specificity
US12404315B2 (en) 2020-12-21 2025-09-02 Allogene Therapeutics, Inc. Protease-activating CD45-gate CAR
WO2022140388A1 (en) 2020-12-21 2022-06-30 Allogene Therapeutics, Inc. Protease-activating cd45-gate car
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
WO2022165233A1 (en) 2021-01-29 2022-08-04 Allogene Therapeutics, Inc. KNOCKDOWN OR KNOCKOUT OF ONE OR MORE OF TAP2, NLRC5, β2m, TRAC, RFX5, RFXAP AND RFXANK TO MITIGATE T CELL RECOGNITION OF ALLOGENEIC CELL PRODUCTS
WO2022215011A1 (en) 2021-04-07 2022-10-13 Novartis Ag USES OF ANTI-TGFβ ANTIBODIES AND OTHER THERAPEUTIC AGENTS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
WO2022229853A1 (en) 2021-04-27 2022-11-03 Novartis Ag Viral vector production system
WO2023009712A1 (en) * 2021-07-29 2023-02-02 Ajax Therapeutics, Inc. Heteroaryloxy thiazolo azines as jak2 inhibitors
WO2023021477A1 (en) 2021-08-20 2023-02-23 Novartis Ag Methods of making chimeric antigen receptor–expressing cells
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
WO2023091954A2 (en) 2021-11-19 2023-05-25 The Trustees Of The University Of Pennsylvania Engineered pan-leukocyte antigen cd45 to facilitate car t cell therapy
WO2023214325A1 (en) 2022-05-05 2023-11-09 Novartis Ag Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors
WO2024026445A1 (en) 2022-07-29 2024-02-01 Allogene Therapeutics Inc. Engineered cells with reduced gene expression to mitigate immune cell recognition
WO2024089639A1 (en) 2022-10-26 2024-05-02 Novartis Ag Lentiviral formulations
US12311022B2 (en) 2023-03-31 2025-05-27 AbelZeta Inc. Bispecific chimeric antigen receptors targeting CD20 and BCMA
US12458667B2 (en) 2023-03-31 2025-11-04 AbelZeta Inc. Bispecific chimeric antigen receptors targeting CD20 and BCMA
WO2024243441A1 (en) 2023-05-24 2024-11-28 Kumquat Biosciences Inc. Heterocyclic compounds and uses thereof
WO2025008108A1 (en) * 2023-07-06 2025-01-09 Miltenyi Biotec B.V. & Co. KG Immune cell expressing chimeric antigen receptor and transgenic t cell receptor
WO2025096560A1 (en) 2023-10-30 2025-05-08 Allogene Therapeutics, Inc. Engineered cells

Also Published As

Publication number Publication date
JP2017522880A (ja) 2017-08-17
CN107109419A (zh) 2017-08-29
TWI719942B (zh) 2021-03-01
CN112481283A (zh) 2021-03-12
EP3722316A1 (en) 2020-10-14
US10851166B2 (en) 2020-12-01
MX390943B (es) 2025-03-21
US12338287B2 (en) 2025-06-24
CA2955154C (en) 2023-10-31
ES2805475T3 (es) 2021-02-12
US20180044423A1 (en) 2018-02-15
CN107109419B (zh) 2020-12-22
RU2017105160A3 (cg-RX-API-DMAC7.html) 2019-02-18
IL250138B (en) 2021-01-31
RU2747384C2 (ru) 2021-05-04
US20210139595A1 (en) 2021-05-13
US9777061B2 (en) 2017-10-03
AU2015292755B2 (en) 2020-11-12
RU2017105160A (ru) 2018-08-21
JP6831777B2 (ja) 2021-02-17
JP2021087430A (ja) 2021-06-10
AU2015292755A1 (en) 2017-02-02
SG10201913765YA (en) 2020-03-30
EP3172234B1 (en) 2020-04-08
AU2021200929A1 (en) 2021-03-04
TW201619379A (zh) 2016-06-01
IL250138A0 (en) 2017-03-30
BR112017001242A2 (pt) 2017-12-05
SG11201700416TA (en) 2017-02-27
MX2017001008A (es) 2017-08-02
US20250353916A1 (en) 2025-11-20
CO2017000510A2 (es) 2017-06-30
EP3172234A1 (en) 2017-05-31
ZA201700157B (en) 2020-03-25
US20160096892A1 (en) 2016-04-07
KR102594343B1 (ko) 2023-10-26
KR20170029009A (ko) 2017-03-14
CA2955154A1 (en) 2016-01-28

Similar Documents

Publication Publication Date Title
US20250353916A1 (en) Treatment of cancer using a cd33 chimeric antigen receptor
US20230220090A1 (en) Treatment of cancer using a cd123 chimeric antigen receptor
US20200215171A1 (en) Treatment of cancer using a cll-1 chimeric antigen receptor
HK40035924A (en) Treatment of cancer using a cd123 chimeric antigen receptor
HK1231901B (en) Treatment of cancer using a cd33 chimeric antigen receptor
HK1231901A1 (en) Treatment of cancer using a cd33 chimeric antigen receptor
HK1238262B (en) Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment
HK1238262A1 (en) Anti-cd123 chimeric antigen receptor (car) for use in cancer treatment

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15745069

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2955154

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 250138

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2017503497

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: NC2017/0000510

Country of ref document: CO

Ref document number: MX/A/2017/001008

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112017001242

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 2015292755

Country of ref document: AU

Date of ref document: 20150721

Kind code of ref document: A

REEP Request for entry into the european phase

Ref document number: 2015745069

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2015745069

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 20177004379

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2017105160

Country of ref document: RU

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 112017001242

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20170119