Suicide module compositions and methods
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Publication Number
US-12103956-B2
Publication Date
2024-10-01
Expiration Date
Abstract
Chimeric transmembrane proteins comprising one or more suicide modules and methods of making and using these constructs are disclosed. The chimeric transmembrane proteins comprise one or more suicide module and a transmembrane domain. Engineered cells comprising such chimeric transmembrane proteins and methods of using such engineered cells are also disclosed.
Core Innovation
The invention relates to a chimeric transmembrane protein that includes a suicide module. The suicide module comprises a ligand binding domain comprising the B cell maturation antigen extracellular domain and a transmembrane domain, and the chimeric transmembrane protein comprises an amino acid sequence selected from SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51.
The disclosed architecture further combines the suicide module with a chimeric antigen receptor. A chimeric antigen receptor comprising a single-chain immunoglobulin variable fragment and a chimeric antigen receptor signaling domain is incorporated into the chimeric transmembrane protein, and in some embodiments the suicide module is positioned between the single-chain immunoglobulin variable fragment and the chimeric antigen receptor signaling domain.
The invention also includes a method of selectively killing an engineered adoptive cell by ligand-triggered activation of the suicide module. The method includes engineering an adoptive cell by introducing the suicide module containing the B cell maturation antigen extracellular domain ligand binding domain and the transmembrane domain, introducing the engineered adoptive cell into a subject, and introducing a ligand capable of binding the ligand binding domain, thereby resulting in killing of the engineered adoptive cell.
Claims Coverage
The document contains two independent claims covering 2 inventive features: a chimeric transmembrane protein suicide module architecture with specified amino acid sequence selections, and a ligand-triggered method for selectively killing engineered adoptive cells by introducing the engineered cell into a subject and administering a binding ligand.
Chimeric transmembrane protein with BCMA extracellular domain suicide module
A chimeric transmembrane protein comprising a suicide module comprising a ligand binding domain comprising the B cell maturation antigen extracellular domain and a transmembrane domain, wherein the chimeric transmembrane protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51.
Ligand-triggered selective killing of engineered adoptive cells with BCMA suicide module
A method of selectively killing an engineered adoptive cell comprising engineering the adoptive cell by introducing a suicide module into the adoptive cell, wherein the suicide module comprises a ligand binding domain comprising the B cell maturation antigen extracellular domain and a transmembrane domain, wherein the chimeric transmembrane protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51; introducing the engineered adoptive cell into a subject; and introducing into the subject a ligand capable of binding the ligand binding domain, thereby resulting in killing of the engineered adoptive cell.
Overall claim coverage centers on a BCMA extracellular domain-containing suicide module fused into a chimeric transmembrane protein with a transmembrane domain and a specified set of amino acid sequences, and on selective killing by administering a ligand that binds the suicide module ligand binding domain after introducing engineered adoptive cells into a subject.
Stated Advantages
Allows mitigation of toxicities associated with engineered adoptive cells, including GvHD, CRS, and neurotoxicity.
Documented Applications
Selectively depleting engineered adoptive cells to mitigate toxicities associated with engineered adoptive cells, including GvHD, CRS, and neurotoxicity.
Use of ligand-triggered killing in a subject by introducing an engineered adoptive cell comprising the suicide module and introducing a ligand capable of binding the ligand binding domain, thereby resulting in killing of the engineered adoptive cell.
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