Methods and compositions for reducing the immunogenicity of chimeric notch receptors
AssigneeCell Design Labs, Inc.
InventorsPeter Emtage, Amy E. Gilbert, Anselm Levskaya, Spencer Scott, Vladimir Slepushkin
Life of this patent
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Abstract
The present invention relates to methods and compositions for reducing the immunogenicity of chimeric Notch receptors, and specifically to transcription factors useful for controlling gene expression delivered to tissues by such chimeric Notch receptors.
Claims22
A method of treating a CD19-expressing cancer in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a T cell expressing a chimeric Notch polypeptide comprising from N-terminal to C-terminal and in covalent linkage:
- a) an extracellular domain comprising a binding agent that specifically binds to human CD19;
- b) a human Notch 2 or human Notch 3 core domain comprising one or more proteolytic cleavage sites;
- and
- c) an intracellular domain comprising a transcriptional regulator comprising a DNA binding domain of human origin and a transactivation domain of human origin;
- and
- wherein said T cell also comprises a nucleic acid construct comprising a cognate DNA binding sequence for the DNA binding domain of human origin, a promoter sequence, and a nucleic acid sequence encoding either a cytokine that locally induces and recruits immune cells to the CD19-expressing cancer or a chimeric antigen receptor (CAR) that targets an antigen other than CD19 on cancer cells in the human subject.
A method of treating a CD19-expressing cancer in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a T cell expressing a chimeric Notch polypeptide comprising from N-terminal to C-terminal and in covalent linkage:
- a) an extracellular domain comprising an scFv that specifically binds to human CD19;
- b) a human Notch 3 core domain comprising one or more proteolytic cleavage sites;
- and
- c) an intracellular domain comprising a transcriptional regulator comprising a human HNF1α DNA binding domain and a human RelA (p65) transactivation domain;
- and
- wherein said T cell also comprises a nucleic acid construct comprising a cognate DNA binding sequence for the HNF1a DNA binding domain, a promoter sequence, and a nucleic acid sequence encoding either a cytokine that locally induces and recruits immune cells to the CD19-expressing cancer or a chimeric antigen receptor (CAR) that targets an antigen other than CD19 on cancer cells in the human subject.
A method of treating a CD19-expressing cancer in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of a macrophage expressing a chimeric Notch polypeptide comprising from N-terminal to C-terminal and in covalent linkage:
- a) an extracellular domain comprising a binding agent that specifically binds to human CD19;
- b) a human Notch 2 or human Notch 3 core domain comprising one or more proteolytic cleavage sites;
- c) an intracellular domain comprising a transcriptional regulator comprising a DNA binding domain of human origin and a transactivation domain of human origin;
- and
- wherein said macrophage also comprises a nucleic acid construct comprising a cognate DNA binding sequence for the DNA binding domain of human origin, a promoter sequence, and a nucleic acid sequence encoding either a cytokine that locally induces and recruits immune cells to the CD19-expressing cancer or a chimeric antigen receptor (CAR) that targets an antigen other than CD19 on cancer cells in the human subject.
Dependencies are inferred from the claim text.