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RU-2861671-C2 - METHOD FOR SELECTING UNIVERSAL DONOR FOR IDENTIFYING NK CELL DONORS

RU2861671C2RU 2861671 C2RU2861671 C2RU 2861671C2RU-2861671-C2

Abstract

FIELD: biotechnology; medicine. SUBSTANCE: invention relates to methods for selecting universal donor NK cells, including for therapeutic administration to a subject, for preparing a population and obtaining a collection of such cells, as well as to an engineered NK cell for treating acute myeloid leukaemia. EFFECT: universal source of NK cells not suffering from compatibility issues. 37 cl, 9 dwg, 3 tbl, 4 ex

Inventors

  • LEE, DEAN

Dates

Publication Date
20260507
Application Date
20200914
Priority Date
20200911

Claims (20)

  1. 1. A method for selecting universal donor NK cells from a donor, comprising: selecting candidate NK cells having (i) an HLA genotype carrying the HLA alleles C1, C2, and Bw4, and (ii) a KIR genotype or phenotype having KIR inhibitory 2DL1, 2DL2, and 3DL1, or a KIR genotype or phenotype having KIR inhibitory 2DL1, 2DL3, and 3DL1, as universal donor NK cells.
  2. 2. The method according to paragraph 1, further comprising:
  3. selection of candidate NK cells having the KIR genotype containing the KIR activating 2DS1 and 3DS1 as universal donor NK cells.
  4. 3. The method according to paragraph 1 or 2, further comprising:
  5. a) assessment of the expression of 2DL1, 2DL2 or 2DL3, and 3DL1 in candidate NK cells;
  6. b) obtaining the HLA genotype of candidate NK cells; and/or
  7. c) obtaining the KIR genotype of candidate NK cells.
  8. 4. The method according to any one of claims 1-3, further comprising selecting a donor having a CMV seropositive profile as a source of candidate NK cells.
  9. 5. The method according to claim 4, wherein the selected universal donor NK cells are NKG2C+.
  10. 6. The method according to any one of claims 1-5, wherein the selected universal donor NK cells are activated by incubating the universal donor NK cells in vitro in the presence of IL-21.
  11. 7. The method according to claim 6, wherein IL-21 comprises at least one of soluble IL-21, IL-21 expressing feeder cells (FC21), IL-21 plasma membrane particles (PM21), and IL-21 exosomes (EX21).
  12. 8. The method of claim 7, wherein the IL-21 present on feeder cells (FC21), IL-21 plasma membrane particles (PM21), and IL-21 exosomes (EX21) comprises a form of IL-21 selected from (a) an engineered membrane-bound form for IL-21, (b) IL-21 chemically conjugated to the surface of FC21, PM21, or EX21, or (c) IL-21 in solution mixed to be in co-contact with NK cells, and wherein any of FC21, PM21, or EX21 further comprises (a) one or more activating agents, stimulatory peptides, cytokines, and/or adhesion molecules selected from 4-1BBL, IL-2, IL-12, IL-18, IL-15, IL-7, ULBP, MICA, LFA-1, 2B4, BCM/SLAMF2, CCR7, OX40L, NKG2D agonists, delta-1, Notch ligands, NKp46 agonists, NKp44 agonists, NKp30 agonists, other NCR agonists, CD16 agonists; or (b) membrane-bound TGF-β.
  13. 9. The method of claim 8, wherein any of FC21, PM21 and EX21 further comprises 4-1BBL.
  14. 10. A method of administering universal donor NK cells to a subject, wherein the subject is administered universal donor NK cells selected to have (i) an HLA genotype carrying the HLA alleles C1, C2, and Bw4, and (ii) a KIR genotype or phenotype having the KIR inhibitory 2DL1, 2DL2, and 3DL1, or a KIR genotype or phenotype having the KIR inhibitory 2DL1, 2DL3, and 3DL1.
  15. 11. The method according to claim 10, wherein the universal donor NK cells are obtained from a donor having a CMV seropositive profile.
  16. 12. The method according to claim 10 or 11, wherein the universal donor NK cells are activated by incubating the universal donor NK cells in vitro in the presence of IL-21.
  17. 13. The method according to claim 12, wherein IL-21 comprises at least one of soluble IL-21, IL-21 expressing feeder cells (FC21), IL-21 plasma membrane particles (PM21), and IL-21 exosomes (EX21).
  18. 14. The method of claim 13, wherein the IL-21 present on FC21, PM21, and EX21 comprises a form of IL-21 selected from (a) an engineered membrane-bound form for IL-21, (b) IL-21 chemically conjugated to the surface of FC21, PM21, or EX21, or (c) IL-21 in solution mixed to be in co-contact with NK cells, and wherein any of FC21, PM21, or EX21 further comprises (a) one or more activating agents, stimulatory peptides, cytokines, and/or adhesion molecules selected from 4-1BBL, IL-2, IL-12, IL-18, IL-15, IL-7, ULBP, MICA, LFA-1, 2B4, BCM/SLAMF2, CCR7, OX40L, NKG2D agonists, delta-1, Notch ligands, NKp46 agonists, NKp44 agonists, NKp30 agonists, other NCR agonists, CD16 agonists; or (b) membrane-bound TGF-β.
  19. 15. The method of claim 14, wherein any of FC21, PM21 and EX21 further comprises 4-1BBL.
  20. 16. A method for selecting NK cells from a universal donor, comprising:

Description

CROSS-REFERENCES TO RELATED APPLICATIONS This application claims the benefit of copending U.S. Provisional Patent Application Serial No. 62/900,245, filed September 13, 2019, entitled A UNIVERSAL DONOR SELECTION ALGORITHM TO IDENTIFY NK CELL DONORS WITH IDEAL CHARACTERISTICS FOR ANY RECIPIENT, and copending U.S. Provisional Patent Application Serial No. 63/049,325, filed July 8, 2020, entitled UNIVERSAL DONOR SELECTION METHOD TO IDENTIFY NK CELL DONORS, under 35 U.S.C. § 119(e). AREA OF TECHNOLOGY The present invention relates generally to a method for selecting a donor for natural killer (NK) cells and, more particularly, to a method for selecting universal donor cells for therapeutic administration to a recipient in need thereof. LEVEL OF TECHNOLOGY Human natural killer (NK) cells express multiple receptors that interact with human leukocyte antigen (HLA) class I molecules. These NK cell receptors belong to one of two major protein superfamilies: the immunoglobulin superfamily or the C-type lectin superfamily. The ability of NK cells to differentiate normal from pathological tissue is largely explained by the inhibitory function of the killer cell immunoglobulin-like receptor (KIR) family, which preferentially recognizes classical HLA class I molecules on potential targets. This recognition of their major histocompatibility complex (MHC) confers functional competence to the NK cell to activate its activating receptors, a process called licensing. As a result, licensed NK cells with MHC-specific receptors are more easily activated than unlicensed NK cells without MHC-specific receptors. Different members of the KIR family interact with discrete HLA class I allotypes and exhibit extensive genetic diversity. Similarly, NK cells simultaneously express multiple receptors with different specificities. Consequently, any attempt to use NK cells in adoptive immunotherapy must address compatibility between the NK cell donor and recipient. Testing multiple donors to identify the right donor for a specific patient can be costly and time-consuming. A universal source of NK cells that is free from compatibility issues is essential. ESSENCE OF THE INVENTION In one aspect, the present invention relates to a method for selecting universal donor NK cells for therapeutic administration to a subject in need thereof, comprising: determining a KIR phenotype of candidate NK cells from an NK cell donor, wherein the KIR phenotype is indicative of the presence of one or more variably inherited inhibitory KIRs 2DL1, 2DL2, 2DL3 and 3DL1; and selecting the candidate NK cells as universal donor NK cells for therapeutic administration, wherein the KIR phenotype is indicative of the presence of one or more variably inherited inhibitory KIRs 2DL1, 2DL2, 2DL3 and 3DL1. In another aspect, the present invention relates to a method for selecting universal donor NK cells for therapeutic administration to a recipient subject in need thereof, comprising: obtaining an HLA genotype of candidate NK cells from an NK cell donor, wherein the HLA genotype is indicative of the presence or absence of at least two HLA alleles C1, C2 and Bw4, and thus, indicative of the presence of one or more variably inherited inhibitory KIRs 2DL1, 2DL2, 2DL3 and 3DL1; and selecting the candidate NK cells as universal donor NK cells for therapeutic administration, when the HLA genotype of the candidate NK cells is indicative of the presence of at least two of the HLA alleles C1, C2 and Bw4. The method may further comprise obtaining or having the obtained KIR phenotype of candidate NK cells, wherein the KIR phenotype is indicative of the presence or absence of activating KIRs selected from the group consisting of 2DS1/2, 2DS3/5, 3DS1 and 2DS4; and further selecting the candidate NK cells, wherein the candidate NK cells containing at least three activating KIRs 2DS1/2, 2DS3/5, 3DS1 and/or 2DS4 are universal NK cells. The method may further comprise obtaining or having the obtained HLA genotype of candidate NK cells from an NK cell donor, where the HLA genotype is indicative of the presence or absence of HLA alleles C1, C2 and Bw4 and thus, indicative of the presence of one or more variably inherited inhibitory KIR 2DL1, 2DL2, 2DL3 and 3DL1 and further selecting the candidate NK cells as universal donor NK cells for therapeutic administration, when the HLA genotype is indicative of the presence of at least two HLA alleles from HLA C1, C2 and Bw4. The present invention also relates to a method for selecting universal donor NK cells for therapeutic administration to a recipient subject in need thereof, comprising obtaining or having obtained a KIR genotype of candidate NK cells, wherein the KIR genotype is indicative of the presence or absence of activating KIRs selected from the group consisting of 2DS1/2, 2DS3/5, 3DS1 and 2DS4, and selecting the candidate NK cells as universal donor NK cells for therapeutic administration, when the KIR genotype is indicative of the presenc