Methods for treating cancer or modulating T cells or NK cells in a subject with cancer by administering cells comprising chimeric cytokine receptors
AssigneeAutolus Limited
InventorsMartin Pulé, Shaun Cordoba, Matteo Righi, James Sillibourne, Shimobi Onuoha, Simon Thomas
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Abstract
The present invention provides a chimeric cytokine receptor (CCR) comprising: (i) an exodomain which binds to a ligand selected from a tumour secreted factor, a chemokine and a cell-surface antigen; and (ii) a cytokine receptor endodomain.
Claims27
A method for treating a subject for cancer, which comprises the step of administering a pharmaceutical composition to a subject in need of treatment for the cancer,
- said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR) and a chimeric antigen receptor (CAR),
- (A) wherein said chimeric cytokine receptor comprises a first and a second chimeric transmembrane polypeptide, wherein:
- (i) the first chimeric transmembrane polypeptide comprises:
- (a) a first exodomain which comprises an antigen-binding domain of an antibody which binds a first epitope of a ligand;
- (b) a first transmembrane domain;
- and
- (c) a first cytokine receptor endodomain;
- and
- (ii) the second chimeric transmembrane polypeptide comprises:
- (a) a second exodomain which comprises an antigen-binding domain of an antibody which binds a second epitope of the ligand;
- (b) a second transmembrane domain;
- and
- (c) a second cytokine receptor endodomain;
- wherein the ligand is a tumour secreted factor;
- and
- wherein the first cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain;
- and wherein the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor;
- and
- (B) wherein the CAR comprises an antigen-binding domain, a spacer domain, a transmembrane domain, and an endodomain, wherein the antigen-binding domain specifically binds a tumour-associated antigen (TAA).
A method for treating a subject for cancer, which comprises the step of administering a pharmaceutical composition to a subject in need of treatment for cancer, said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR) and a chimeric antigen receptor (CAR),
- (A) wherein said CCR comprises a first and a second chimeric transmembrane polypeptide, wherein:
- (i) the first chimeric transmembrane polypeptide comprises:
- (a) a first exodomain which comprises a heavy chain variable domain (VH) of an antibody that binds to the ligand;
- (b) a first transmembrane domain;
- and
- (c) a first cytokine receptor endodomain;
- and
- (ii) the second chimeric transmembrane polypeptide comprises:
- (a) a second exodomain which comprises a light chain variable domain (VL) of the antibody that binds to the ligand;
- (b) a second transmembrane domain;
- and
- (c) a second cytokine-receptor endodomain;
- wherein the ligand is a tumour secreted factor;
- and
- wherein one of the first cytokine receptor endodomain and the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain;
- and wherein the other of the first cytokine receptor endodomain and the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor;
- and
- (B) wherein the CAR comprises an antigen-binding domain, a spacer domain, a transmembrane domain, and an endodomain, wherein the antigen-binding domain specifically binds a tumour-associated antigen (TAA).
A method of modulating a T cell or NK cell response in a subject with cancer, the method comprising the step of administering a pharmaceutical composition to a subject,
- said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR), said chimeric cytokine receptor comprising a first and a second chimeric transmembrane polypeptide, wherein:
- (i) the first chimeric transmembrane polypeptide comprises:
- (a) a first exodomain which comprises an antigen-binding domain of an antibody which binds a first epitope of a ligand;
- (b) a first transmembrane domain;
- and
- (c) a first cytokine receptor endodomain;
- and
- (ii) the second chimeric transmembrane polypeptide comprises:
- (a) a second exodomain which comprises an antigen-binding domain of an antibody which binds a second epitope of the ligand;
- (b) a second transmembrane domain;
- and
- (c) a second cytokine receptor endodomain;
- wherein the ligand is a tumour secreted factor;
- and
- wherein one of the first cytokine receptor endodomain and the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain;
- and wherein the other of the first cytokine receptor endodomain and the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor.
A method of modulating a T cell or NK cell response in a subject with cancer, the method comprising the step of administering a pharmaceutical composition to a subject, said pharmaceutical composition comprising a plurality of T cells or NK cells, said T cells or NK cells comprising a chimeric cytokine receptor (CCR), said CCR comprising a first and a second chimeric transmembrane polypeptide, wherein:
- (i) the first chimeric transmembrane polypeptide comprises:
- (a) a first exodomain which comprises a heavy chain variable domain (VH) of an antibody that binds to the ligand;
- (b) a first transmembrane domain;
- and
- (c) a first cytokine receptor endodomain;
- and
- (ii) the second chimeric transmembrane polypeptide comprises:
- (a) a second exodomain which comprises a light chain variable domain (VL) of the antibody that binds to the ligand;
- (b) a second transmembrane domain;
- and
- (c) a second cytokine-receptor endodomain;
- wherein the ligand is a tumour secreted factor;
- and
- wherein one of the first cytokine receptor endodomain and the second cytokine receptor endodomain is an IL-2 receptor β-chain endodomain, an IL-7 receptor α-chain endodomain, or an IL-15 receptor α-chain endodomain;
- and wherein the other of the first cytokine receptor endodomain and the second cytokine receptor endodomain is a γ-chain receptor endodomain of an IL-2 receptor, an IL-7 receptor, or an IL-15 receptor.
Dependencies are inferred from the claim text.