Modified natural killer cells that express IL15 and uses thereof
AssigneesNational University of Singapore, St. Jude Children's Research Hospital
InventorsDario Campana, David Shook, Masaru Imamura
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Abstract
The present invention provides, in certain aspects, a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15), and methods for producing such cells. The invention further provides methods of using a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15) to treat cancer in a subject or to enhance expansion and/or survival of NK cells.
Claims15
A natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15), wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell, and wherein the all or a functional portion of IL-15 promotes one or more of:
- (i) NK cell survival,
- (ii) regulation of NK cell and T cell activation and proliferation, and
- (iii) support of NK cell development from hematopoietic stem cells.
A composition comprising a Natural Killer (NK) cell and a physiologically acceptable carrier or excipient,
- wherein the NK cell expresses all or a functional portion of interleukin-15 (IL-15),
- wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell, and
- wherein the all or a functional portion of IL-15 promotes one or more of:
- (i) NK cell survival,
- (ii) regulation of NK cell and T cell activation and proliferation, and
- (iii) support of NK cell development from hematopoietic stem cells.
A pharmaceutical composition comprising a Natural Killer (NK) cell and a pharmaceutically acceptable carrier,
- wherein the NK cell expresses all or a functional portion of interleukin-15 (IL-15),
- wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell, and
- wherein the all or a functional portion of IL-15 promotes one or more of:
- (i) NK cell survival,
- (ii) regulation of NK cell and T cell activation and proliferation, and
- (iii) support of NK cell development from hematopoietic stem cells.
A pharmaceutical composition comprising a Natural Killer (NK) cell, a pharmaceutically acceptable carrier, and all or a functional portion of IL-2,
- wherein the NK cell expresses all or a functional portion of interleukin-15 (IL-15),
- wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell,
- wherein the all or a functional portion of IL-15 promotes one or more of:
- (i) NK cell survival,
- (ii) regulation of NK cell and T cell activation and proliferation, and
- (iii) support of NK cell development from hematopoietic stem cells, and
- wherein the IL-2, or functional portion of IL-2, is present in an amount effective to increase expansion of the NK cell in vitro or in vivo.
A natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15) as a membrane-bound polypeptide,
- wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mb15) of the NK cell,
- wherein the transmembrane protein is selected from the group consisting of CD8α, CD4, CD3ε, CD3γ, CD3δ, CD3ζ, CD28, CD137, glycophorin A, glycophorin D, nicotinic acetylcholine receptor, a GABA receptor, FcεRIγ, and a T-cell receptor, and
- wherein the NK cell exhibits enhanced survival and expansion in the absence of IL-2, as compared to NK cells not expressing membrane-bound IL15.
A Natural Killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15), wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell, and wherein the all or a functional portion of IL-15 promotes one or more of:
- (i) NK cell survival,
- (ii) regulation of NK cell and T cell activation and proliferation, and
- (iii) support of NK cell development from hematopoietic stem cells, and
- wherein the all or a functional portion of the IL-15 comprises the amino acid sequence of SEQ ID NO:
- 4.
A Natural Killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15), wherein the all or a functional portion of the IL-15 is fused to all or a portion of a transmembrane protein that anchors the expressed IL-15 as a cell membrane-bound polypeptide (mbIL15) of the NK cell, and wherein the all or a functional portion of IL-15 promotes one or more of:
- (i) NK cell survival,
- (ii) regulation of NK cell and T cell activation and proliferation, and
- (iii) support of NK cell development from hematopoietic stem cells,
- wherein the NK cell is produced by a method comprising:
- introducing a nucleic acid encoding all or a functional portion of IL-15 fused to all or a portion of a transmembrane protein into the NK cell;
- and
- maintaining the NK cell under conditions in which the all or a functional portion of the IL-15 is expressed, thereby producing a NK cell that expresses the all or a functional portion of IL-15 fused to all or a portion of a transmembrane protein, and wherein the nucleic acid comprises SEQ ID NO:
- 1.
Dependencies are inferred from the claim text.