Modified effector cell (or chimeric receptor) for treating disialoganglioside G
A modified effector cell includes a non-reversibly produced vector-encoded anti-G D2 -BB-ζ chimeric receptor for use in disialoganglioside G D2 -expressing neoplasia, which is inserted in the cell, to obtain an effector cell that stably produces the anti-G D2 -BB-ζ chimeric receptor, the chimeric receptor having two distinct mutually fused portions, i.e. an intra-cytoplasmic portion and an extra-cytoplasmic portion.
1. A modified effector cell for treating disialoganglioside GD 2 -expressing neoplasia, comprising:
a cytoplasm with a nucleus therein, the cytoplasm being enclosed in a membrane; and
a chimeric receptor, wherein the chimeric receptor comprises an extracytoplasmic portion, a transmembrane portion, and an intracytoplasmic portion,
wherein the extracytoplasmic portion comprises, in order:
a signal peptide containing an intron sequence,
a first sequence encoding for a variable region of a light chain of the anti-GD 2 immunoglobulin M (IgM) antibody,
a linker that allows folding of a GD 2 antigen recognition region of an anti-GD 2 IgM antibody, and
a second sequence encoding for a variable region of a heavy chain of the anti-GD 2 IgM antibody, and
wherein the transmembrane portion and the intracytoplasmic portion comprise, in order:
a hinge and transmembrane domain of a human lymphocyte CD8α molecule,
an intracellular portion of a 4-1BB co-stimulatory molecule, and
an intracellular portion of a human lymphocyte CD3-ζ molecule.
2. The modified effector cell as claimed in claim 1 , wherein the chimeric receptor is encoded by the sequence set forth in SEQ ID NO: 1.
3. The modified effector cell as claimed in claim 1 , wherein the linker that allows folding of the GD 2 antigen recognition region consists of 18 amino acids.
4. The modified effector cell as claimed in claim 1 , wherein the anti-GD 2 IgM antibody is from clone 126.
5. A polyclonal mixture of effector cells for treating disialoganglioside GD 2 -expressing neoplasia, comprising:
a plurality of modified effector cells comprising:
a cytoplasm with a nucleus therein, the cytoplasm being enclosed in a membrane; and
a chimeric receptor, wherein the chimeric receptor comprises an extracytoplasmic portion, a transmembrane portion, and an intracytoplasmic portion,
wherein the extracytoplasmic portion comprises, in order:
a signal peptide containing an intron sequence,
a first sequence encoding for a variable region of a light chain of the anti-GD 2 immunoglobulin M (IgM) antibody,
a linker that allows folding of a GD 2 antigen recognition region of an anti-GD 2 IgM antibody, and
a second sequence encoding for a variable region of a heavy chain of the anti-GD 2 IgM antibody,
wherein the transmembrane portion and the intracytoplasmic portion comprise, in order:
a hinge and transmembrane domain of a human lymphocyte CD8α molecule,
an intracellular portion of a 4-1BB co-stimulatory molecule, and
an intracellular portion of a human lymphocyte CD3-ζ molecule, and
wherein at least 20% of the modified effector cells comprises a CD3+/CD8+/CD56+ phenotype.
6. The polyclonal mixture of effector cells as claimed in claim 5 , wherein the chimeric receptor is encoded by the sequence set forth in SEQ ID NO: 1.
7. The polyclonal mixture of effector cells as claimed in claim 5 , wherein the linker that allows folding of the GD 2 antigen recognition region consists of 18 amino acids.
8. The polyclonal mixture of effector cells as claimed in claim 5 , wherein the anti-GD 2 IgM antibody is from clone 126.