Compositions and methods for promoting hematopoietic cell cytotoxicity
Inventors
Spencer, Harold Trent • DOERING, CHRISTOPHER • Chandrakasan, Shanmuganathan • FLEISCHER, Lauren • Zoine, Jaquelyn • Branella, Gianna • Brown, Harrison C.
Assignees
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Publication Number
US-12551558-B2
Publication Date
2026-02-17
Expiration Date
Abstract
Provided herein are compositions and methods for promoting hematopoietic cell cytotoxicity.
Core Innovation
The disclosure uses a ligand-based chimeric antigen receptor approach in which thrombopoietin (TPO) is linked to a CH3 hinge, and the resulting recombinant protein further comprises a transmembrane domain and a CD3-zeta signaling domain. The TPO linked to the CH3 hinge is encoded by a codon optimized nucleic acid having the nucleic acid sequence of SEQ ID NO: 15.
The disclosure includes vector embodiments that comprise a nucleic acid sequence encoding the same TPO-CH3 hinge recombinant protein architecture encoded by the codon optimized nucleic acid with the nucleic acid sequence of SEQ ID NO: 15. The disclosure further describes refinements including a CD28 transmembrane domain, an N-terminal IL-2 signal sequence, and defined components corresponding to domain sequence identifiers.
The description frames the approach as addressing leukemia treatment using ligand-based CAR/NSCAR constructs targeting hematopoietic and leukemia cell surface receptors, including MPL with thrombopoietin (TPO) and c-KIT with stem cell factor (SCF). The constructs are described as comprising engineered transmembrane and signaling components, or lacking intracellular signaling for NSCAR.
The documented examples include contexts such as acute myelogenous leukemia and show CAR-mediated and NSCAR outcomes directed to receptor-associated cell states, including efforts described as minimizing NSCAR fratricide/product self-killing while enhancing killing by gamma delta T cells.
Claims Coverage
Two independent claims are provided. One claim covers a leukemia treatment method using cells expressing a specific TPO-CH3 hinge CAR architecture encoded by SEQ ID NO: 15, and the other claim covers a vector encoding the same architecture.
Ligand-based TPO-CH3 hinge CAR treatment of leukemia using codon-optimized SEQ ID NO: 15 cells
A method for treating leukemia in which cells obtained from a first subject are provided by introducing a nucleic acid construct encoding a recombinant protein comprising thrombopoietin (TPO) linked to a CH3 hinge, a transmembrane domain, and CD3-zeta signaling domain, wherein the TPO linked to a CH3 hinge is encoded by a codon optimized nucleic acid having the nucleic acid sequence of SEQ ID NO: 15, and administering an effective amount of the cells expressing the recombinant protein to a second subject diagnosed with leukemia; the administered cells are selected from alpha beta T cells, cytotoxic T lymphocytes, T helper cells, lymphokine-activated cells, tumor-infiltrating lymphocytes, NK cells, naïve T cells, memory T cells, gamma delta T cells, NKT cells, and macrophages.
Vector encoding codon-optimized TPO-CH3 hinge recombinant protein with SEQ ID NO: 15
A vector comprising a nucleic acid sequence encoding a recombinant protein comprising thrombopoietin (TPO) linked to a CH3 hinge encoded by a codon optimized nucleic acid having the nucleic acid sequence of SEQ ID NO: 15.
Across the independent claims, the core inventive coverage centers on codon optimized nucleic acid sequence SEQ ID NO: 15 encoding a recombinant protein with thrombopoietin (TPO) linked to a CH3 hinge, combined with engineered transmembrane and CD3-zeta signaling components for a leukemia treatment method, and alternatively provided as a vector encoding that same architecture.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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