Enhancement of natural killer (NK) cell proliferation and activity
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Publication Number
US-9175266-B2
Publication Date
2015-11-03
Expiration Date
Abstract
Methods of ex-vivo culture of natural killer (NK) cells are provided and, more particularly, methods for enhancing propagation and/or functionality of NK cells by treating the cells with an aryl hydrocarbon antagonist in combination with cytokines driving NK cell proliferation. Also envisioned are compositions comprising cultured NK cells and therapeutic uses thereof.
Core Innovation
The invention relates to a method of ex-vivo culturing a population of cells comprising NK cells by culturing the population with an aryl hydrocarbon receptor (AHR) antagonist represented by Formula I. The Formula I antagonist has defined selections for G1, R3, G2, G3, G4, L, R1, R2, and R4, with provisos that at least one of G3 and G4 is N, G1 and G2 are not both N, and R1 and R3 are not both hydrogen.
L is selected from a substituted or unsubstituted alkylamino, a substituted or unsubstituted amino, or a substituted or unsubstituted alkyl. R1 is selected from hydrogen, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl, and R2 is selected from specified thio- or amino-containing groups and substituted aryl and heteroaryl options. R4 is selected from substituted or unsubstituted C1-10 alkyl, C1-10 alkenyl, cycloalkyl, aryl, alkaryl, heteroalicyclic, and heteroaryl.
The method is described as supporting NK cell outcomes including increased CD62L expression, decreased CD200R and/or PD-1 expression, increased homing and in-vivo retention, greater proliferation, enhanced NK proliferation and functionality, reduced CD3+ expansion, improved engraftment and persistence, and dose-dependent expansion and altered cell composition in ex-vivo culture. Specific embodiments identify Stem Reginin 1 (SR1) and other substituted AHR antagonist structures within the Formula I framework.
Claims Coverage
The independent claim covers ex-vivo culturing of NK cells with an AHR antagonist defined by Formula I and explicit structural constraints across G1, R3, G2, G3, G4, L, R1, R2, and R4. Dependent claims further narrow the AHR antagonist to specific embodiments and specify culturing parameter ranges and comparative outcomes, giving coverage across structure selection, culturing conditions, and functional readouts.
Ex-vivo culturing NK cells with a formula I AHR antagonist
A method of ex-vivo culturing a population of cells comprising NK cells by culturing the population with an aryl hydrocarbon receptor (AHR) antagonist represented by Formula I, with provisos that at least one of G3 and G4 is N, G1 and G2 are not both N, and R1 and R3 are not both hydrogen.
Specific AHR antagonist embodiments within formula I
The method uses specific substituted AHR antagonist compounds within the Formula I framework, including Stem Reginin 1 (SR1).
AHR antagonist concentration range
The AHR antagonist is used at a concentration ranging from 1 to 100000 nM.
Culturing time period range
Culturing is performed for a time period ranging from 3 days to 6 weeks.
Comparative NK phenotype and functional outcomes versus culturing without the AHR antagonist
Culturing NK cells with the AHR antagonist produces at least one of increased CD62L expression, decreased CD200R and/or PD-1 expression, increased homing and in-vivo retention, greater proliferation, reduced CD3+ expansion, improved engraftment, and persistence versus culturing without the AHR antagonist.
Overall, the claims center on ex-vivo culturing NK cells using a Formula I-defined AHR antagonist, with dependent claims specifying exemplary embodiments, concentration and time ranges, and comparative outcomes including CD62L, CD200R, PD-1, homing, in-vivo retention, proliferation, CD3+ expansion, engraftment, and persistence versus culturing without the AHR antagonist.
Stated Advantages
Increased CD62L expression versus culturing without the AHR antagonist.
Decreased CD200R and/or PD-1 expression versus culturing without the AHR antagonist.
Increased homing and in-vivo retention versus culturing without the AHR antagonist.
Greater proliferation versus culturing without the AHR antagonist.
Enhanced NK proliferation and functionality.
Reduced CD3+ expansion.
Improved engraftment and persistence.
Documented Applications
Ex-vivo culturing of a population of cells comprising NK cells using an AHR antagonist represented by Formula I.
Modulating NK cell phenotype and function in culture, including CD62L, CD200R, and/or PD-1 expression, homing, in-vivo retention, proliferation, engraftment, and persistence relative to culturing without the AHR antagonist.
Therapeutic use for tumor growth inhibition.
Therapeutic use for viral infection.
Therapeutic use for GVHD.
Therapeutic use for leukemia.
Therapeutic use for autoimmune diseases.
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