Compositions and methods for selective elimination and replacement of hematopoietic stem cells
Inventors
Ostertag, Eric M. • Shedlock, Devon • Down, Julian David
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11744861-B2
Publication Date
2023-09-05
Expiration Date
Abstract
Disclosed are methods of eliminating at least on target cell in a subject, comprising administering to the subject an effective amount of a composition comprising a plurality of immune cells, wherein each immune cell of the plurality expresses one or more chimeric ligand receptor(s) (CLR(s)) that each specifically bind to a target ligand on the at least one target cell, wherein specifically binding of the one or more CLR(s) to the target activates the immune cell, and wherein the activated immune cell induces death of the target cell. Exemplary target cells include, but are not limited to, hematopoietic stem cells (HSCs).
Core Innovation
The invention provides a method of eliminating at least one target hematopoietic stem cell in a subject by administering an effective amount of a composition containing a plurality of T-cells that express at least one chimeric ligand receptor (CLR). The CLR specifically binds to c-KIT, and the specific binding activates the T-cell, which induces death of the at least one target HSC.
The CLR comprises an ectodomain that includes a human CD8α signal peptide, a scFv comprising the amino acid sequence of SEQ ID NO: 73, and a human CD8α hinge domain. The CLR additionally includes a transmembrane domain comprising a human CD8α transmembrane domain, a co-stimulatory domain comprising a human 4-1BB costimulatory domain, and an endodomain comprising a human CD3ζ endodomain.
The disclosure also describes a drug-reversible approach in which CLR/CAR-expressing immune cells can be eliminated after ablation of recipient HSCs. It further emphasizes a safety switch concept and non-genotoxic conditioning for HSC transplantation to enable niche opening for donor therapeutic HSC engraftment.
Claims Coverage
The independent claim set covers a method of eliminating target hematopoietic stem cells using a composition of T-cells that express a CLR specifically binding c-KIT, where CLR binding activates the T-cells to induce death of the target HSC. Three inventive features are explicitly defined across the claims.
C-KIT-binding CLR-activated T-cell HSC elimination method
A method of eliminating at least one target hematopoietic stem cell in a subject by administering an effective amount of a composition comprising a plurality of T-cells that express at least one CLR that specifically binds to c-KIT, wherein the specific binding activates the T-cell and the activated T-cell induces death of the at least one target HSC.
Human CD8α-based CLR architecture with CD3ζ endodomain
The CLR comprises an ectodomain comprising a human CD8α signal peptide, a scFv comprising the amino acid sequence of SEQ ID NO: 73, and a human CD8α hinge domain, a transmembrane domain comprising a human CD8α transmembrane domain, a co-stimulatory domain comprising a human 4-1BB costimulatory domain, and an endodomain comprising a human CD3ζ endodomain.
Drug-reversible safety switch concept
CLR/CAR-expressing immune cells can be eliminated after ablation of recipient HSCs, with the disclosure emphasizing a safety switch concept and non-genotoxic conditioning for HSC transplantation to enable niche opening for donor therapeutic HSC engraftment.
Overall, the claims are centered on CLR-expressing T-cells whose c-KIT-specific binding activates the T-cells to induce death of target HSCs, with the CLR architecture explicitly defined using human CD8α structural components plus a 4-1BB co-stimulatory domain and a CD3ζ endodomain. The disclosure also includes a drug-reversible safety switch concept and non-genotoxic conditioning for HSC transplantation.
Stated Advantages
Enables selective elimination of target hematopoietic stem cells by activating CLR-expressing T-cells upon specific binding to c-KIT.
Employs a drug-reversible approach in which CLR/CAR-expressing immune cells can be eliminated after ablation of recipient HSCs.
Uses non-genotoxic conditioning for HSC transplantation to enable niche opening for donor therapeutic HSC engraftment.
Documented Applications
Treating cancer, including lymphoma, leukemia, myeloma, or malignant immunoproliferative disease.
Interested in licensing this patent?