NZ712351B2 - Cd123-specific chimeric antigen receptor redirected t cells and methods of their use - Google Patents
Cd123-specific chimeric antigen receptor redirected t cells and methods of their useInfo
- Publication number
- NZ712351B2 NZ712351B2 NZ712351A NZ71235114A NZ712351B2 NZ 712351 B2 NZ712351 B2 NZ 712351B2 NZ 712351 A NZ712351 A NZ 712351A NZ 71235114 A NZ71235114 A NZ 71235114A NZ 712351 B2 NZ712351 B2 NZ 712351B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- amino acid
- seq
- acid substitution
- polypeptide
- signaling domain
- Prior art date
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- 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
- A61K2239/10—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the structure of the chimeric antigen receptor [CAR]
- A61K2239/17—Hinge-spacer domain
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- 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
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- 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
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- 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
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- 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]
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- 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
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- 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
- C07K2317/60—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)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2510/00—Genetically modified cells
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
Abstract
family of chimeric antigen receptors (CARs) containing a CD123 specific scFv was developed to target different epitopes on CD123. In some embodiments, such a CD123 chimeric antigen receptor (CD123CAR) gene includes an anti-CD123 scFv region fused in frame to a modified IgG4 hinge region comprising an S228P substitution, an L235E substitution, and an N297Q substitution; a costimulatory signaling domain; and a T cell receptor (TCR) zeta chain signaling domain. When expressed in healthy donor T cells (CD4/CD8), the CD123CARs redirect T cell specificity and mediated potent effector activity against CD123+ cell lines as well as primary AML patient samples. Further, T cells obtained from patients with active AML can be modified to express CD123CAR genes and are able to lyse autologous AML blasts in. Finally, a single dose of 5.0 x 10vitro CAR123 T cells results in significantly delayed leukemic progression in mice. These results suggest that CD123CAR-transduced T cells may be used as an immunotherapy for the treatment of high risk AML.
Description
CD123-SPECIFIC CHIMERIC ANTIGEN RECEPTOR REDIRECTED T CELLS AND METHODS OF THEIR USE PRIORITY
Claims (18)
1. A c acid molecule encoding a CD123 chimeric antigen receptor (CD123CAR) ptide comprising: an anti-CD123 scFv region; an IgG4 hinge region comprising SEQ ID NO: 13 having an N to Q amino acid substitution at position 79 and an L to E amino acid substitution at position 17, and an S to P amino acid substitution at position 10; and a T cell receptor (TCR) zeta chain ing domain.
2. The nucleic acid molecule of claim 1, wherein the anti-CD123 scFv region is humanized.
3. The nucleic acid molecule of claim 1, wherein the AR ptide further comprises at least one costimulatory signaling domain selected from a CD27 costimulatory signaling domain, a CD28 costimulatory signaling domain, a 4-1BB ulatory ing domain, a OX40 costimulatory signaling domain, or any combination thereof.
4. The nucleic acid le of claim 1, wherein the CD123CAR polypeptide further comprises a transmembrane domain and, optionally, wherein the transmembrane domain is a modified CD28 transmembrane domain.
5. The nucleic acid molecule of claim 1, wherein the CD123CAR polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:11 and SEQ ID NO:12.
6. The nucleic acid molecule of claim 1 comprising nucleotide sequence selected from the group consisting of: SEQ ID NO:3 and SEQ ID NO:4.
7. An expression cassette comprising a nucleotide sequence encoding a CD123 chimeric antigen or (CD123CAR) polypeptide comprising: an anti-CD123 scFv region; an IgG4 hinge region comprising SEQ ID NO: 13 having an N to Q amino acid substitution at position 79 and an L to E amino acid substitution at position 17, and an S to P amino acid substitution at position 10; and a T cell or (TCR) zeta chain signaling domain.
8. The expression cassette of claim 7 r sing a nucleotide sequence encoding an accessory gene selected from the group consisting of: a truncated epidermal growth factor receptor (EGFRt), a truncated CD19 (CD19t) or caspase 9.
9. An isolated in vitro population of human T cells transduced by a viral vector comprising the expression cassette comprising a nucleotide sequence encoding a CD123 chimeric antigen receptor (CD123CAR) polypeptide comprising: an anti-CD123 scFv region; an IgG4 hinge region comprising SEQ ID NO: 13 having an N to Q amino acid substitution at position 79 and an L to E amino acid substitution at on 17, and an S to P amino acid substitution at position 10; and a T cell or (TCR) zeta chain signaling domain.
10. The use of a pharmaceutical composition for the manufacture of a medicament for the treatment of acute myeloid leukemia (AML) in a t, said medicament comprising a population of T cells transduced by a vector comprising the expression cassette comprising a nucleotide sequence encoding a CD123 chimeric n receptor CAR) polypeptide comprising: an anti-CD123 scFv region; an IgG4 hinge region comprising SEQ ID NO: 13 having an N to Q amino acid substitution at position 79 and an L to E amino acid substitution at position 17, and an S to P amino acid substitution at position 10; and a T cell receptor (TCR) zeta chain signaling domain.
11. The use of claim 10, wherein the T cells are autologous T cells.
12. The use of claim 10, wherein the medicament is adapted for administration via parenteral ion.
13. A polypeptide comprising a CD123 ic antigen receptor (CD123 CAR) comprising: an anti-CD123 scFv region; an IgG4 hinge region comprising SEQ ID NO: 13 having an N to Q amino acid substitution at position 79 and an L to E amino acid substitution at position 17, and an S to P amino acid substitution at position 10; and a T cell receptor (TCR) zeta chain signaling domain.
14. The polypeptide of claim 13, wherein the D123 scFv region is humanized.
15. The polypeptide of claim 13, wherein the CD123 CAR polypeptide further ses at least one costimulatory signaling domain selected from a CD27 costimulatory signaling domain, a CD28 ulatory ing domain, a 4-1BB costimulatory signaling , a OX40 costimulatory signaling domain, or any combination thereof.
16. The polypeptide of claim 13, wherein the CD123 CAR polypeptide further comprises a transmembrane domain and, optionally, wherein the transmembrane domain is a modified CD28 transmembrane domain.
17. The polypeptide of claim 13, wherein the CD123 CAR polypeptide comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:11 and SEQ ID NO:12.
18. The polypeptide of claim 13 encoded by a nucleotide sequence selected from the group consisting of: SEQ ID NO:3 and SEQ ID NO:4.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/844,048 US9657105B2 (en) | 2013-03-15 | 2013-03-15 | CD123-specific chimeric antigen receptor redirected T cells and methods of their use |
| PCT/US2014/029109 WO2014144622A2 (en) | 2013-03-15 | 2014-03-14 | Cd123-specific chimeric antigen receptor redirected t cells and methods of their use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ712351A NZ712351A (en) | 2021-07-30 |
| NZ712351B2 true NZ712351B2 (en) | 2021-11-02 |
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