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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/10—Cellular immunotherapy characterised by the cell type used
  • A61K40/15—Natural-killer [NK] cells; Natural-killer T [NKT] cells
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K40/00—Cellular immunotherapy
  • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
  • A61K40/41—Vertebrate antigens
  • A61K40/42—Cancer antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
  • C07K16/244—Interleukins [IL]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
  • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
  • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
  • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
  • A61K2239/48—Blood cells, e.g. leukemia or lymphoma
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

• greater than 10% of the cells in the g-NK cell composition are capable of producing interferon-gamma or TNF-alpha against tumor target cells, optionally wherein the interferon-gamma or TNF-alpha may be measured in the absence of an antibody against the tumor target cells.
• the cells in the g-NK cell composition greater than at or about 15%, greater than at or about 20%, greater than at or about 30%, greater than at or about 40% or greater than at or about 50% produce an effector cytokine in the presence of cells expressing a target antigen (target cells) and an antibody directed against the target antigen (anti-target antibody).
• FIG. 8D shows g-NK cell degranulation levels against the MM.1S cell line.
• FIG. 8E and FIG. 8F depict levels of perforin and granzyme B expression in g-NK cells expanded in the presence of various cytokine mixtures and concentrations.
• FIG. 8E shows perforin and granzyme B expression as percentages of g-NK cells.
• FIG. 8F shows total perforin and granzyme B expression.
• FIG. 8G and FIG. 8H depict daratumumab- and elotuzumab-mediated Interferon- ⁇ expression levels of g-NK cells expanded in the presence of various cytokine mixtures and concentrations.
• FIG. 8G and FIG. 8H depict daratumumab- and elotuzumab-mediated Interferon- ⁇ expression levels of g-NK cells expanded in the presence of various cytokine mixtures and concentrations.
• FIG. 8G and FIG. 8H depict daratumumab- and e
• the g-NK cells have a prolonged lifespan, compared to conventional NK cells, and their presence is maintained long-term.
• g-NK cells are functionally and phenotypically stable.
• g-NK cells are more effective in eliciting ADCC responses than conventional NK cells, e.g. NK cells that are not deficient in the ⁇ chain.
• g-NK cells are more effective in eliciting cell-mediated cytotoxicity than are conventional NK cells even in the absence of antibody.
• ADCC is a mechanism of action of therapeutic antibodies, including anti-cancer antibodies.
• cell therapy by administering NK cells can be used in concert with antibodies for therapeutic and related purposes.
• compositions address these needs.
• Provided herein are methods involving combined administration of a composition containing g- NK cells, e.g. as produced by the provided methods, and an antibody, e.g. an anti- cancer antibody.
• antibody-directed targeting of g- NK cells leads to improved outcomes for patients due to the improved affinity, cytotoxic and/or cytokine- mediated effect functions of the g- NK cell subset.
• Methods described herein are able to produce NK cell compositions enriched in g- NK cells that overcome these limitations.
• the provided methods utilize a greater ratio of HLA- E+ feeder cells deficient in HLA class I and HLA class II, for instance 221.AEH cells, to NK- cells compared to previous methods.
• previous methods have used a lower ratio of 221.AEH cells, such as a ratio of 10:1 NK cell to 221.AEH ratio.
• NK cells The high persistence and enhanced survival of the NK cells and their resistance to fratricide in this model may support the superior anti-tumor effects and persistence of the g-NK cells.
• enrichment of NK cells from a cell sample prior to the expansion method such as by enrichment for CD16 or CD57 cells prior to expansion, further substantially increases the amount of g-NK cell expansion that can be achieved compared to methods that initially enrich NK cells based on CD3 depletion alone.
• another enrichment that can be carried out prior to expansion is enriching for NK cells by positive selection for CD56 and negative selection or depletion for CD38.
• the provided methods can result in high-yield (>1000 fold) expansion rates with maintained or, in some cases, increased functionality of the g-NK cells after expansion.
• the provided methods can result in a g-NK cell population expressing high levels of perforin and granzyme B.
• the provided methods are sufficient to expand previously frozen NK cells, which is not commonly achieved by many existing methods that involve rescue of thawed NK cells. In some embodiments, this is achieved by increasing the duration of the expansion protocol. In some embodiments, this is achieved by decreasing the ratio of HLA-E+ feeder cells to NK cells, e.g. to about 1:1221.AEH to NK cells.
• the provided compositions include those in which the NKG2C pos NKG2A neg cells or a subset thereof make up at least at or about 60%, at least at or about 70%, at least at or about 80%, at least at or about 85%, at least at or about 90%, at least at or about 95% or more of the cells in the composition or of the NK cells in the composition.
• the composition comprises about 5-99% g- NK cells, or any percentage of g- NK cells between 5 and 99% inclusive.
• the individual dose is or is about 5 x 10 8 cells. In some embodiments, the individual dose is or is about 1 x 10 9 cells. In some embodiments, the individual dose is or is about 5 x 10 9 cells. In some embodiments, the individual dose is or is about 1 x 10 10 cells. In any of the above embodiments, the dose is given as the number of cells g-NK cells or an NK cell subset that is associated with or includes a surrogate marker for g-NK cells, such as any of the NK cell subsets described above, or a number of viable cells of any of the foregoing.
• Humanization is accomplished by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody (Jones et al., 1986; Riechmann et al., 1988; Verhoeyen et al., 1988).
• Such “humanized” antibodies are chimeric antibodies (1989), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species.
• humanized antibodies are typically human antibodies in which some CDR residues and possibly some Fc residues are substituted by residues from analogous sites in rodent antibodies.
• Humanized antibodies include human antibodies (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit, having the desired specificity, affinity and capacity. In some instances, corresponding non-human residues replace Fv framework residues of the human antibody. Humanized antibodies may comprise residues that are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which most if not all of the CDR regions correspond to those of a non-human Ig and most if not all of the FR regions are those of a human antibody consensus sequence.
• the g-NK cell composition exhibits minimal anti-CD38-induced fratricide, optionally wherein less than 10% of cells in the g-NK cell composition exhibit anti-CD38 induced fratricide.
• the cells of the present invention can be targeted to tumors by administration with an antibody that recognizes a tumor associated antigen that is SLAMF7.
• the method further includes administering to the subject an anti-SLAMF7 antibody.
• the methods are for treating multiple myeloma.
• the antibody is elotuzumab (e.g. EMPLICITI®).
• the elotuzumab may be administered in an amount that may be at or about 10 mg/kg weekly for two cycles and every 2 weeks thereafter.
• the anti-SLAMF7 antibody is administered with lenalidomide and dexamethasone.
• the anti-SLAMF7 antibody is administered after dexamethasone, diphenhydramine, rantidine, and acetaminophen.
• the method includes administering the anti-SLAMF7 antibody, once weekly for 8 total doses and administering the g-NK cell composition once weekly for 6 total doses, wherein one dose or two doses of the anti-SLAMF7 antibody may be administered prior to administration of the composition including g-NK cells.
• the anti-CD30 antibody may be administered in a cycling regiment. In some embodiments, the antibody is administered in a 28-day cycle. In some embodiments, the antibody is administered once weekly in at least one cycle, such as each cycle. In some embodiments, the antibody is administered once weekly for 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks or more. In some embodiments, eight (8) once weekly doses of the antibody is administered. In some embodiments, the once weekly doses are administered in consecutive weeks. [0252] In some embodiments, the anti-CD30 antibody may be administered intravenously. In some embodiments, the anti-CD30 antibody may be administered subcutaneously.
• BsAbs are bispecific T cell engagers (BiTEs) and bispecific Natural Killer cell engagers (BiKEs).
• BiKEs have been generated to engage CD16 on a Natural Killer cell and a second tumor antigen, and various examples of BiKEs targeting CD16 and a second tumor antigen have been described in the literature (Felices, et al. (2016) Methods Mol. Bio., 1441:333-346).
• BiKEs have been developed for CD16 with CD19 or CD20 in B cell Non-Hodgkin’s lymphomas (Glorius, et al. (2013) Leukemia, 27:190-201; Kipriyanov, et al. (2002), J.
• the g- NK cells may be administered first, followed by administration of the cytokines and/or growth factors. In some embodiments, the g- NK cells are administered simultaneously with the cytokines or growth factors.
• the subject is administered one or more cytokines (such as IL-2, IL- 15, IL-21, IL-27, and/or IL-12) to support survival and/or growth of NK cells.
• the cytokine(s) can be administered before, after, or substantially simultaneously with the NK cells. In some examples, the cytokine(s) can be administered after the NK cells.
• the fludarabine can be administered in a single dose or can be administered in a plurality of doses, such as given daily, every other day or every three days.
• the cyclophosphamide is administered once daily for one or two days.
• the subject is administered fludarabine at a dose between or between about 1 mg/m 2 and 100 mg/m 2 , such as between or between about 10 mg/m 2 and 75 mg/m 2 , 15 mg/m 2 and 50 mg/m 2 , 20 mg/m 2 and 30 mg/m 2 , or 24 mg/m 2 and 26 mg/m 2 .
• the cells are isolated or selected from a sample, such as a biological sample, e.g., one obtained from or derived from a subject, such as one having a particular disease or condition or in need of a cell therapy or to which cell therapy will be administered.
• a sample such as a biological sample, e.g., one obtained from or derived from a subject, such as one having a particular disease or condition or in need of a cell therapy or to which cell therapy will be administered.
• the subject is a human, such as a subject who is a patient in need of a particular therapeutic intervention, such as the adoptive cell therapy for which cells are being isolated, processed, and/or engineered.
• the cells in some embodiments are primary cells, e.g., primary human cells.
• the samples include tissue, fluid, and other samples taken directly from the subject.
• the biological sample can be a sample obtained directly from a biological source or a sample that is processed.
• the blood cells collected from the subject are washed, e.g., to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps.
• the cells are washed with phosphate buffered saline (PBS).
• PBS phosphate buffered saline
• the wash solution lacks calcium and/or magnesium and/or many or all divalent cations.
• components of a blood cell sample are removed and the cells directly resuspended in culture media.
• a subject is selected if the percentage of g-NK cells, or of an NK cell subset that is associated with or includes a surrogate marker for g-NK cells, among NK cells in the biological sample is greater than at or about 18%. In some embodiments, a subject is selected if the percentage of g-NK cells, or of an NK cell subset that is associated with or includes a surrogate marker for g-NK cells, among NK cells in the biological sample is greater than at or about 20%.
• FAM or VIC on the 5’ end and a minor groove binder (MGB) and nonfluorescent quencher (NFQ) on the 3’ end and an unlabeled PCR primers to detect a specific SNP targets.
• the assay measures or detects the presence of an SNP by a change in fluorescence of the dyes associated with the probe.
• probes hybridize to the target DNA between the two unlabeled primers and signal from the fluorescent dye on the 5’ end is quenched by the NFQ on its 3’ end by fluorescence resonance energy transfer (FRET).
• FRET fluorescence resonance energy transfer
• negative selection, removal, or depletion of cells of a particular type refers to decreasing the number or percentage of such cells, but need not result in a complete removal of all such cells.
• a negative selection for CD3 enriches for a population of cells that are CD3 neg , but also can contain some residual or small percentage of other non-selected cells, which can, in some cases, include a small percentage of cells still being present in the enriched population that are CD3 pos .
• the method comprises administering IL-12, IL- 15, IL-18, IL-2 and/or CCL5 to the subject prior to enriching, such as selecting and/or isolating, the NK cells or subset thereof.
• an antigen-binding fragment may comprise 1, 2, 3, 4, 5, or all 6 CDRs of a variable heavy chain (VH) and variable light chain (VL) sequence from antibodies that bind the antigen, such as generally six CDRs for an antibody containing a VH and a VL (“CDR1,” “CDR2” and “CDR3” for each of a heavy and light chain), or three CDRs for an antibody containing a single variable domain.
• An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
• the concentration of recombinant IL-18 during at least a portion of the culturing is between about 1 ng/mL and about 50 ng/mL.
• the concentration of recombinant IL-18 during at least a portion of the culturing, e.g. added at the initiation of the culturing and optionally one or more times during the culturing is at or about 10 ng/mL.
• the concentration of recombinant IL-27 during at least a portion of the culturing e.g.
• the methods include adding recombinant IL-2 at the initiation of the incubation (day 0), and every two or three days at each wash or exchange of the culture medium for the duration of the incubation, e.g. at or about at day 5, day 7, day 9, day 11, and day 14 of the culture or incubation.
• the recombinant IL-27 is added to the culture or incubation at a concentration of between about 1 ng/mL and about 50 ng/mL, between about 1 ng/mL and about 40 ng/mL, between about 1 ng/mL and about 30 ng/mL, between about 1 ng/mL and about 20 ng/mL, between about 1 ng/mL and about 10 ng/mL, between about 1 ng/mL and about 5 ng/mL, between about 5 ng/mL and about 50 ng/mL, between about 5 ng/mL and about 40 ng/mL, between about 5 ng/mL and about 30 ng/mL, between about 5 ng/mL and about 20 ng/mL, between about 5 ng/mL and about 10 ng/mL, between about 10 ng/mL and about 50 ng/mL, between about 10 ng/mL and about 40 ng/mL, between about 10 ng/mL and
• Perfusions can continuously add media to the cells to ensure an optimal growth rate is achieved.
• the expansion methods can be carried out under GMP conditions, including in a closed automated system and using serum free medium.
• any one or more of the steps of the method can be carried out in a closed system or under GMP conditions.
• all process operations are performed in a GMP suite.
• a closed system is used for carrying out one or more of the other processing steps of a method for manufacturing, generating or producing a cell therapy.
• NK cells in the expanded population are FcR ⁇ neg .
• greater than at or about 60% of NK cells in the expanded population are FcR ⁇ neg .
• greater than at or about 70% of NK cells in the expanded population are FcR ⁇ neg .
• greater than at or about 80% of NK cells in the expanded population are FcR ⁇ neg .
• greater than at or about 90% of NK cells in the expanded population are FcR ⁇ neg .
• greater than at or about 95% of NK cells in the expanded population are FcR ⁇ neg .
• the methods herein generally result in a highly pure, e.g.
• the provided methods also can include isolating or enriching g-NK, such as g-NK cells preferentially expanded in accord with any of the provided methods.
• g-NK such as g-NK cells preferentially expanded in accord with any of the provided methods.
• a substantially pure population of g-NK cells can be obtained, such as a cell population containing greater than or greater than about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more g-NK cells, such as determined using any of the described panel or combinations of markers.
• Antibodies and other binding molecules can be used to detect the presence or absence of expression levels of marker proteins, for use in isolating or enriching g ⁇ NK cells.
• the article of manufacture or kit may further include other materials desirable from a commercial, therapeutic, and user standpoint, including other buffers, diluents, filters, needles, syringes, therapeutic agents and/or package inserts with instructions for use.
• the kit can, optionally, include instructions. Instructions typically include a tangible expression describing the cell composition, reagents and/or antibodies and, optionally, other components included in the kit, and methods for using such.
• the instructions indicate methods for using the cell compositions and antibodies for administration to a subject for treating a disease or condition, such as in accord with any of the provided embodiments.
• the instructions are provided as a label or a package insert, which is on or associated with the container.
• the method further comprises administering to the subject an antibody that is directed against a multiple myeloma antigen.
• the multiple myeloma antigen comprises an antigen selected from the group consisting of CD38, SLAMF7, and BCMA.
• the antibody is a full-length antibody.
• the method of any one of embodiments 3-5, wherein the antibody is an anti- SLAMF7 antibody.
• the method of any one of embodiments 3-5, wherein the antibody is an anti- BCMA antibody.
• the method of any one of embodiments 3-5, wherein the antibody is an anti- CD38 antibody.
• the antibody is a bispecific antibody. 10.
• the g-NK cells are not engineered with an antigen receptor, optionally wherein the antigen receptor is a chimeric antigen receptor.
• the g-NK cells are not engineered with a secretable cytokine, optionally a cytokine receptor fusion protein, such as IL- 15 receptor fusion (IL-15RF) 88.
• IL-15RF IL- 15 receptor fusion
• NK cells expanded in the presence of IL-21 had greater cell-mediated cytotoxicity against the CD38 high MM cell line LP1 (FIG. 9G) and the SLAMF7 high MM cell line MM.1S (FIG. 9H) than did g-NK cells expanded without IL-21. Greater cell-mediated cytotoxicity for IL-21 expanded g-NK cells was observed in the absence of antibody as well as in the presence of either daratumumab or elotuzumab. [0451] Together, these results show that g-NK cells expanded in the presence of IL-21 have enhanced cell-mediated cytotoxicity against tumor cells compared to g-NK cells expanded without IL-21.
• C. Degranulation As shown in FIG. 9I and FIG.

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