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Manufacturing NK cell products for clinical researchCliniMACS® System and MACS® GMP Products
Germany/Austria Miltenyi Biotec GmbH Friedrich-Ebert-Straße 68 51429 Bergisch Gladbach Germany Phone +49 2204 8306-0 Fax +49 2204 85197 [email protected]
USA/CanadaMiltenyi Biotec Inc. 2303 Lindbergh Street Auburn, CA 95602, USA Phone 800 FOR MACS Phone +1 530 888 8871 Fax +1 877 591 1060 [email protected]
AustraliaMiltenyi Biotec Australia Pty. Ltd. Unit 16 A, 2 Eden Park Drive Macquarie Park NSW 2113 Australia Phone +61 2 8877 7400 Fax +61 2 9889 5044 [email protected]
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ChinaMiltenyi Biotec Technology & Trading (Shanghai) Co., Ltd. Rooms 2303 and 2309 No. 319, Xianxia Road Changning District 200051 Shanghai, P.R. China Phone +86 21 62351005 Fax +86 21 62350953 [email protected]
FranceMiltenyi Biotec SAS 10 rue Mercoeur 75011 Paris, France Phone +33 1 56 98 16 16 Fax +33 1 56 98 16 17 [email protected]
ItalyMiltenyi Biotec S.r.l. Via Paolo Nanni Costa, 3040133 Bologna Italy Phone +39 051 6 460 411 Fax +39 051 6 460 499 [email protected]
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www.miltenyibiotec.com
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Miltenyi Biotec provides products and services worldwide. Visit www.miltenyibiotec.com/local to find your nearest Miltenyi Biotec contact.
Unless otherwise specifically indicated, Miltenyi Biotec products and services are for research use only and not for therapeutic or diagnostic use. MACS® GMP Products are for research use and ex vivo cell culture processing only, and are not intended for human in vivo applications. For regulatory status in the USA, please contact your local representative. MACS GMP Products are manufactured and tested under a quality system certified to ISO 13485 and are in compliance with relevant GMP guidelines. They are designed following the recommendations of USP <1043> on ancillary materials. The CliniMACS® System components, including Reagents, Tubing Sets, Instruments, and PBS/EDTA Buffer, are designed, manufactured and tested under a quality system certified to ISO 13485.In the EU, the CliniMACS System components are available as CE-marked medical devices for their respective intended use, unless otherwise stated. The CliniMACS Reagents and Biotin Conjugates are intended for in vitro use only and are not designated for therapeutic use or direct infusion into patients. The CliniMACS Reagents in combination with the CliniMACS System are intended to separate human cells. Miltenyi Biotec as the manufacturer of the CliniMACS System does not give any recommendations regarding the use of separated cells for therapeutic purposes and does not make any claims regarding a clinical benefit. For the manufacturing and use of target cells in humans the national legislation and regulations – e.g. for the EU the Directive 2004/23/EC (“human tissues and cells”), or the Directive 2002/98/EC (“human blood and blood components”) – must be followed. Thus, any clinical application of the target cells is exclusively within the responsibility of the user of a CliniMACS System. All CliniMACS Product Line solutions described in this leaflet are available for use only under an approved Investigational New Drug (IND) application or Investigational Device Exemption (IDE). CliniMACS MicroBeads are for research use only and not for human therapeutic or diagnostic use. CliniMACS, CliniMACS Prodigy, MACS, MACSQuant, REAfinity and the MACS logo are registered trademarks or trademarks of Miltenyi Biotec GmbH and/or its affiliates in various countries worldwide. Copyright © 2019 Miltenyi Biotec GmbH and/or its affiliates. All rights reserved.
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Clinical NK cell research
Natural killer (NK) cells play a major role in immune surveillance and in the early immune response to cancer and infections¹,².
During the last decade, a number of clinical studies using NK cells have been completed. Beneficial anti-tumor responses have been observed, illustrating the safety profile and clinical potential of this treatment³,⁴. With an increasing availability of anti-cancer drugs, the role of NK cell-based approaches in novel combination therapies has rapidly escalated⁵,⁶.
Today, the possibility of implementing new therapeutic protocols using primary, expanded, activated and / or genetically modified NK cells grants exciting opportunities. The safety and feasibility of primary NK cells has been tested in clinical trials³,⁷.
In the future, NK cells (CD3–CD56+) and NKT cells (CD3+CD56+) may be exploited not only for the treatment of hematological malignancies, but also as a therapy option for solid tumors as well as for viral and fungal infections.
This brochure provides information regarding next generation production of NK and NKT cells that may allow optimization of cell products, formulation, and efficacy in clinical research.
Content 4 NK cells in the clinical
research setting Exploit the full potential of the immune system
6 Solutions for every NK cell product Tools for isolation and enrichment
8 Isolation of NK and / or NKT cells Fully automated and reproducible
11 Expansion of NK cells Optimal culture conditions with NK MACS® GMP Medium
12 Analysis of NK cells Solutions to power your NK cell analysis
15 MACS GMP Solutions Optimized isolation, culture and analysis of NK and NKT cells
16 CliniMACS Prodigy® Automated and standardized cell manufacturing
18 Selected references
19 The complete solution for clinical NK cell research
21 Product information
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0.00
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Figure 1: Relapse rates in NK cell-treated and untreated patients*. Patients treated with NK cells with >8 alloreactive clones/100 cells (dashed line), <8 alloreactive clones/100 cells (dotted line), and conventional non-NK cell–treated controls (solid line). Analysis was performed on donor cells before NK cell infusion.
Biology of NK and NKT cellsNK cells constitute the first line of defense against viruses and malignant cells, preventing tumor growth and dissemination¹,². They are able to kill target cells directly by cytotoxic granules and indirectly by antibody-mediated cellular cytotoxicity (ADCC)⁸.
NKT cells are a subset of lymphocytes that bridge the gap between innate and adaptive immunity. They control tumor growth and may be involved in the progression of certain autoimmune diseases, such as diabetes, lupus, multiple sclerosis, atherosclerosis, and allergen-induced asthma²,⁵,⁹.
Clinical applications
TransplantationIt has been observed that NK cells do not induce or initiate graft versus host (GVH) reactions. Hence, various reports describe the use of NK cells in haploidentical peripheral blood stem cell transplantations (PBSCT) as donor lymphocyte infusions (DLI) in order to support engraftment, to drive immune reconstitution, and to prevent relapse³,¹⁰-¹². Diseases targeted in these reports were acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Highlighting the important role of NK cells, a recent study showed that post-transplant cyclophosphamide (PT-Cy) ablates mature NK cells and putatively alloreactive single killer cell immunoglobulin-like receptors (KIR) positive NK cells¹⁴. However, the infusion of expanded NK cells was reported to result in significantly improved NK cell numbers and function, lower viral infections, and low relapse rates post-transplant¹⁵.
NK cells in the clinic settingExploit the full potential of the immune system
Non-transplant settingAML is a clinically challenging malignancy, with a 5-year survival rate of 26%¹³ and high relapse rates after chemotherapy¹⁴. Several studies have used NK cell infusions in young¹⁵ or elderly AML patients as post-complete remission (CR) consolidation strategy⁷,¹⁶. High numbers of alloreactive NK cells were associated with prolonged disease-free survival (figure 1). In this study, nine of 16 CR patients were disease-free after a median follow-up of 27 months, without any additional treatment¹⁶.
Solid tumorsThe promising results of NK cell treatments in hematological diseases make them good candidates for therapies against other types of malignancies, including solid cancers³. The use of NK cells for the treatment of hepatocellular carcinoma¹⁷,¹⁸, colorectal carcinoma, renal cell carcinoma¹⁸, ovarian and breast cancer¹⁹ among others has been reported to be safe and an attractive approach for further clinical evaluation.
Engineered NK cells Pre-clinical studies on engineered NK cells are emerging as a promising therapeutic approach for the treatment of solid tumors and hematological diseases²⁰.
* Adapted from Curti, A. et al. (2016) Larger size of donor Alloreactive NK cell repertoire correlates with better response to NK cell immunotherapy in elderly acute myeloid leukemia patients. Clinical Cancer Research 22: 1914–21 with permission from AACR.
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For more than 20 years, Miltenyi Biotec has provided the tools to generate NK cell preparations. The wide variety of reagents allows to either enrich NK cell preparations or to obtain pure NK cells. The preparations can now be performed in a fully automated way using the CliniMACS Prodigy® Platform.
Solutions for every NK cell product Tools for isolation and enrichment
Desired final productDesired final product
Selected references
Reagents
NK cells and NKT cells
15, 23–26
Steps
CliniMACS CD56 Reagent
NK cells and accessory cells
CD3 only: 27, 28 CD3/CD19: 5
, 29, 3
0
CliniMACS CD19 Reagent
CliniMACS CD3 Reagent
NK
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/δ T
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eagen
tStarting material
1st step: CD3+ cell depletion
2nd step: CD56+ cell enrichment
One-step: CD56+ cell enrichment
One-step: CD3+ cell depletion/ CD19+ cell depletion (optional)
One-step: TCRα/β+ cell depletion/ CD19+ cell depletion (optional)
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Centers and institutes around the world have isolated NK cells using the CliniMACS® Plus System for more than two decades. Miltenyi Biotec now offers a fully automated solution for the isolation of NK cells from leukapheresis products. The CliniMACS Prodigy® (see page 16) facilitates cell processing in a closed system, with minimal hands-on time from the user. The standardized procedure enables robust and consistent results.
CliniMACS Prodigy® CD3 / CD56 System
The CliniMACS Prodigy CD3 / CD56 System combines the features of the CliniMACS Prodigy, the associated tubing sets and buffers with the CliniMACS CD3 and CD56 Reagents. It is designed for the magnetic depletion of CD3+ cells and/or the magnetic enrichment of CD56+ cells from leukapheresis products. It guarantees excellent cell purity, cell viability and a high yield.
Isolation of NK and / or NKT cellsFully automated and reproducible
0
Purity Viability Yield
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Figure 2: Cell purity, viability and yield percentages of CD3–CD56+ cells were measured after isolation from leukapheresis products with the CliniMACS Prodigy CD3 / CD56 System.
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Automated Manual
Figure 3: Proportion of manual and automated process time during cell separation with the CliniMACS Prodigy CD3 / CD56 System.
Starting material Leukapheresis
Purity 94.8% (87.1–98.7%)
Yield 48.3% (28.3–59.9%)
T cell depletion (log) 4.22 (3.92–4.41)
Leuk
aphe
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s product
CD3+ cell depletion and CD56+ cell enrichment
CD3 −CD56 +cell population
Leukapheresis product
T cells
B cellsNK cells
Monocytes
Neutrophils
HSC
Final cell product
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Pure NK cell populations, generated by easy CD3+ cell depletion and subsequent CD56+ cell enrichment on the CliniMACS Prodigy®.
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NK MACS GMP MediumNK MACS® GMP Medium has been specifically developed for NK cell expansion from either PBMCs or isolated NK cells.
• Superior NK cell expansion
• Xeno-free
• Minimal growth of unwanted cells like B, T, and dendritic cells
• QC functionality test on every batch
• Filled in flexible bags (connection via Luer fitting)
• Fully translational, from research (NK MACS Medium) to MACS GMP grade
Functional NK cells after expansionNK cells cultivated in NK MACS Medium retain their natural cytotoxicity against the K-562 cell line and are suitable for any downstream application including cytotoxicity killing assays and flow cytometry analysis.
Expansion of NK cellsOptimal culture conditions with NK MACS® GMP Medium
Figure 4: The expansion rate for NK cells from PBMCs in NK MACS Medium (for research use) and NK MACS GMP Medium is comparable.
Figure 5: NK cell killing assay after 14 days of NK cell expansion. PBMCs were cultivated using NK MACS Medium (research and MACS GMP). At day 14, a standard 4 hour killing assay was performed at different effector:target ratios.
NK
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The phenotypic and functional characterization of NK cells has been of tremendous use in the design of new clinical research platforms. Reproducibility and consistency play an important role in the determination of NK cells in all stages of research, pre-clinical and clinical studies. The wide portfolio of the new REAfinity™ Recombinant Antibodies enables background-free staining, without the need of extensive isotype controls.
Analysis of NK cellsSolutions to power your NK cell analysis
A BMouse monoclonal REA284
– FcR block
+ FcR block
4.90%
10³-101
10¹ 10²0
10³
10²
10¹
CD158a (KIR2DL1)-PE
CD
56-A
PC
-1 1
2.54%
10³-101
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CD158a (KIR2DL1)-PE
CD
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10³-101
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10³
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CD158a (KIR2DL1)-PE
CD
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PC
-1 1
0.06%
10³-101
10¹ 10²0
10³
10²
10¹
CD158a (KIR2DL1)-PE
CD
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PC
-1 1
Figure 6: Staining of NK cells with REAfinity Antibodies. Human PBMCs were stained with either a mouse monoclonal CD158a-PE antibody or REAfinity CD158a-PE (clone:REA284). Staining was performed without (top) and with (bottom) FcR block. The mouse monoclonal antibody binds unspecifically to CD56-negative cells (A). Stainings with the REAfinity Antibody shows no background signal even without FcR block (B). Cells were analyzed by flow cytometry on the MACSQuant® Analyzer 10. Cell debris and dead cells were excluded from the analysis based on scatter signals and propidium iodide (PI) fluorescence.
Made to meet new reproducibility standards
Recombinantly generatedantibodies
Made to eliminate background signal
Mutated Fc region
Made to reduce complexity ofexperiment planning
One universal lgG1 isotype
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KIR typing – from phenotype to genotype
A cell genotype does not necessarily reflect its phenotype. Killer-cell Ig-like receptors (KIR) recognizing HLA I molecules on target cells, are no exception. Get the KIR-specific antibodies you need for KIR phenotyping from Miltenyi Biotec. We have assembled the broadest portfolio of KIR-specific antibodies available. Additionally, you can complement your NK cell phenotyping by flow cytometry with profiling of human KIR genes at the genomic DNA or mRNA level using the KIR Typing Kit.
Marker REA Clones
KIR2D REA1042
CD158a (KIR2DL1) REA284
CD158a/h (KIR2DL1/DS1) REA1010
CD158b2 (KIR2DL3) REA147
CD158b (KIR2DL2/L3) REA1006
CD158i (KIR2DS4) REA860
CD158e (KIR3DL1) REA1005
CD158e1/e2 (KIR3DL1/S1) REA168
CD158d (KIR2DL4) REA768
CD158e/k (KIR3DL1/DL2) REA970
CD158f (KIR2DL5) REA955
The broadest KIR antibody portfolio on the market
TranslationValidationCompliance
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MACS GMP ProductsThe quality of your final cell product is strongly influenced by the raw materials used. For the development of cell-based and gene therapy products regulatory authorities require the adherence to strict procedures in compliance with GMP. MACS® GMP Products are manufactured and tested under a quality management system (ISO 13485) and are in compliance with relevant GMP guidelines. They are designed following the recommendations of USP <1043> on ancillary materials.
MACS® GMP solutionsOptimized isolation, culture and analysis of NK and NKT cells
NK MACS GMP Medium and MACS GMP CytokinesNK MACS GMP Medium has been optimized and designed to expand NK cells together with MACS GMP Cytokines.
MACS GMP Cytokines are highly active and pure recombinant proteins that enable consistent cell culture results. They are lyophilized without carrier protein or preservatives. Highest product standards are ensured by aseptic filling, lyophilization, and rigorous quality control tests. Each product is supplied with a certificate of analysis that confirms the stringent specifications and states the lot-specific biological activity.
• Standardized high biological activities (IU/mg)
• Documentation of every processing step, from development to production and QC testing
• Consistent product quality
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The CliniMACS Prodigy® represents the next generation in automated NK and NKT cell processing. The instrument offers advanced integrated solutions – from cell separation to cell culture and formulation of the final cell product.
CliniMACS Prodigy®Automated and standardized cell manufacturing
Fully automated and scalable cell manufacturing procedures
Standardized software for producing a variety of cell types including NK cells
Cell enrichment and / or depletion using MACS® Technology
Closed system from starting material to final cell product
Reduction of handling steps minimizes the risk of human error and cell loss
Sensor-controlled processes
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Selected references
1. Chiossone, L. et al. (2018) Natural killer cells and other innate lymphoid cells in cancer. Nat. Rev. Immunol. 18: 671–688.
2. Hammer, Q. et al. (2018) Natural killer cell specificity for viral infections. Nat. Immunol. 19: 800-808.
3. Miller, J. S. et al. (2005) Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105: 3051–3057.
4. Curti, A. et al. (2011) Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 118: 3273–3279.
5. Bachanova, V. et al. (2018) Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol. Immunother. 67: 483-94.
6. Talleur, A. C. et al. (2017) Consolidation therapy for newly diagnosed pediatric patients with high-risk neuroblastoma using busulfan/melphalan, autologous hematopoietic cell transplantation, anti-GD2 antibody, granulocyte-macrophage colony-stimulating factor, interleukin-2, and haploidentical natural killer cells. Biol. Blood Marrow Transplant. 23: 1910–1917.
7. Fehniger, T. A. et al. (2018) A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Biol. Blood Marrow Transplant. 24: 1581–1589.
8. Caligiuri, M. A. (2008) Human natural killer cells. Blood. 112: 461–469.
9. Smyk, D. S. et al. (2018) The role of invariant NKT in autoimmune liver disease: Can vitamin D act as an immunomodulator? Can. J. Gastroenterol. Hepatol. 2018: 8197937.
10. Pende, D. et al. (2009) Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood 113: 3119–3129.
11. Ruggeri, L. et al. (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295: 2097–2100.
12. Bari, R. et al. (2013) Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J. Clin. Oncol. 31: 3782–3790.
13. Juliusson, G. et al. (2009) Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 113: 4179–4187.
14. Lemoli, R. M. et al. (2017) Novel strategies of adoptive immunotherapy: How natural killer cells may change the treatment of elderly patients with acute myeloblastic leukemia. Exp. Hematol. 45: 10–16.
15. Rubnitz, J. E. et al. (2010) NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J. Clin. Oncol. 28: 955–959.
16. Curti, A. et al. (2016) Larger size of donor alloreactive NK cell repertoire correlates with better response to NK cell immunotherapy in elderly acute myeloid leukemia patients. Clin. Cancer Res. 22: 1914–1921.
17. Lin, M. et al. (2017) Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer. Oncotarget 8: 81967-81977.
18. Barkholt, L. et al. (2009) Safety analysis of ex vivo-expanded NK and NK-like T cells administered to cancer patients: a phase I clinical study. Immunotherapy 1: 753–764.
19. Geller, M. A. et al. (2011) A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 13: 98–107.
20. Daher, M. et al. (2018) Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. Curr. Opin. Immunol. 51: 146–153.
21. Passweg, J. R. et al. (2004) Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 18: 1835–1838.
22. Federico, S. M. et al. (2017) A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma. Clin. Cancer Res. 23: 6441–6449.
23. Jaiswal, S. R. et al. (2017) CD56-enriched donor cell infusion after post-transplantation cyclophosphamide for haploidentical transplantation of advanced myeloid malignancies is associated with prompt reconstitution of mature natural killer cells and regulatory T cells with reduced incidence of acute graft versus host disease: A pilot study. Cytotherapy 19: 531–542.
24. Kottaridis, P. D. et al. (2015) Two-stage priming of allogeneic natural killer cells for the treatment of patients with acute myeloid leukemia: A phase I trial. PLoS One 10: e0123416.
25. Rizzieri, D. A. et al. (2010) Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation. Biol. Blood Marrow Transplant. 16: 1107–1114.
26. Iliopoulou, E. G. et al. (2010) A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol. Immunother. 59: 1781–1789.
27. Ciurea, S. O. et al. (2017) Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 130: 1857–1868.
28. Adotevi, O. et al. (2018) In situ delivery of allogeneic natural killer cell (NK) combined with Cetuximab in liver metastases of gastrointestinal carcinoma: A phase I clinical trial. Oncoimmunology 7: e1424673.
29. Williams, S. M. et al. (2018) Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution. Transfusion 58: 1458–1467.
30. Bjorklund, A. T. et al. (2018) Complete remission with reduction of high-risk clones following haploidentical NK-cell therapy against MDS and AML. Clin. Cancer Res. 24: 1834–1844.
31. Lang, P. et al. (2015) Improved immune recovery after transplantation of TCRαβ/CD19-depleted allografts from haploidentical donors in pediatric patients. Bone Marrow Transplant. 50 Suppl 2: S6–10.
32. Shah, R. M. et al. (2018) T-cell receptor αβ+ and CD19+ cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency. J. Allergy Clin. Immunol. 141: 1417–1426.
The complete solution for clinical NK cell researchOver the past decades we have developed the widest portfolio for NK cell research on the market and have translated it to clinical research to enable the discovery of new therapeutic tools. We now provide solutions not only for the separation of NK cells but also a complete tool set for culturing and analyzing them. We offer flexibility and fully automated processes to support your research and therapeutic effort. Our processes and reagents are already part of several clinical studies.
NK MACS® GMPMedium
MACS GMPCytokines
NK cell expansionLeukapheresis Cell
enrichment
CliniMACS Prodigy®
CliniMACS® Plus
CliniMACS ProdigyCD3 / CD56 System
19
20
CryoMACS®Freezing Bags
Cryo- preservation
MACSQuant®(RUO)
REAfinity™Recombinant
Antibiodes (RUO)
KIR Typing Kit
NK cell analysis
Ready to use cell product
20
21
Product information
Product Content
CliniMACS Prodigy 1 unit
CliniMACS Plus 1 unit
CliniMACS® InstrumentsProduct Content
CliniMACS CD3 Reagent 7.5 mL
CliniMACS CD56 Reagent 7.5 mL
CliniMACS TCRα/β Kit 1 kit
CliniMACS CD19 Reagent 7.5 mL
CliniMACS Prodigy Tubing Set TS 310 1 set
CliniMACS Prodigy Tubing Set TS 520 1 set
CliniMACS Tubing Set 1 set
CliniMACS Depletion Tubing Set 1 set
CliniMACS PBS/EDTA Buffer 3×1 L or 2×3 L
Products for NK and NKT cell research
KIR analysis
MACS® GMP Media
MACS GMP Cytokines
MACS GMP Consumables
Product Content
KIR Typing Kit 8 tests, 24 tests
Product Content
NK MACS GMP Medium 2,000 mL
Product Capacity
MACS GMP Recombinant Human IL-2 25 µg, 100 µg or 500 µg
MACS GMP Recombinant Human IL-15 25 µg
MACS GMP Recombinant Human IL-21 25 µg
Product Capacity
CryoMACS Freezing Bags 50 mL, 250 mL, 500 mL, 750 mL, and 1,000 mL
Manufacturing NK cell products for clinical researchCliniMACS® System and MACS® GMP Products
miltenyibiotec.com/cliniMACS
Germany/Austria Miltenyi Biotec GmbH Friedrich-Ebert-Straße 68 51429 Bergisch Gladbach Germany Phone +49 2204 8306-0 Fax +49 2204 85197 [email protected]
USA/CanadaMiltenyi Biotec Inc. 2303 Lindbergh Street Auburn, CA 95602, USA Phone 800 FOR MACS Phone +1 530 888 8871 Fax +1 877 591 1060 [email protected]
AustraliaMiltenyi Biotec Australia Pty. Ltd. Unit 16 A, 2 Eden Park Drive Macquarie Park NSW 2113 Australia Phone +61 2 8877 7400 Fax +61 2 9889 5044 [email protected]
BeneluxMiltenyi Biotec B.V. Sandifortdreef 17 2333 ZZ Leiden The Netherlands [email protected] service The NetherlandsPhone 0800 4020120 Fax 0800 4020100Customer service BelgiumPhone 0800 94016 Fax 0800 99626Customer service LuxembourgPhone 800 24971 Fax 800 24984
ChinaMiltenyi Biotec Technology & Trading (Shanghai) Co., Ltd. Rooms 2303 and 2309 No. 319, Xianxia Road Changning District 200051 Shanghai, P.R. China Phone +86 21 62351005 Fax +86 21 62350953 [email protected]
FranceMiltenyi Biotec SAS 10 rue Mercoeur 75011 Paris, France Phone +33 1 56 98 16 16 Fax +33 1 56 98 16 17 [email protected]
ItalyMiltenyi Biotec S.r.l. Via Paolo Nanni Costa, 3040133 Bologna Italy Phone +39 051 6 460 411 Fax +39 051 6 460 499 [email protected]
JapanMiltenyi Biotec K.K. Nittsu-Eitai Building 5F 16-10 Fuyuki, Koto-ku, Tokyo 135-0041, Japan Phone +81 3 5646 8910 Fax +81 3 5646 8911 [email protected]
Nordics and BalticsMiltenyi Biotec Norden AB Scheelevägen 17 223 70 Lund Sweden [email protected] service SwedenPhone 0200-111 800 Fax 046-280 72 99 Customer service DenmarkPhone 80 20 30 10 Fax +46 46 280 72 99 Customer service Norway, Finland, Iceland, and Baltic countriesPhone +46 46 280 72 80 Fax +46 46 280 72 99
SingaporeMiltenyi Biotec Asia Pacific Pte Ltd. 100 Beach Road #28-06 to 28-08 Shaw Tower Singapore 189702 Phone +65 6238 8183 Fax +65 6238 0302 [email protected]
South KoreaMiltenyi Biotec Korea Co., Ltd Arigi Bldg. 8F 562 Nonhyeon-ro Gangnam-gu Seoul 06136, South Korea Phone +82 2 555 1988 Fax +82 2 555 8890 [email protected]
SpainMiltenyi Biotec S.L. C/Luis Buñuel 2 Ciudad de la Imagen 28223 Pozuelo de Alarcón (Madrid) Spain Phone +34 91 512 12 90 Fax +34 91 512 12 91 [email protected]
SwitzerlandMiltenyi Biotec Swiss AG Gibelinstrasse 27 4500 SolothurnSwitzerland Phone +41 32 623 08 47 Fax +49 2204 85197 [email protected]
United KingdomMiltenyi Biotec Ltd. Almac House, Church Lane Bisley, Surrey GU24 9DR, UK Phone +44 1483 799 800 Fax +44 1483 799 811 [email protected]
www.miltenyibiotec.com
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Miltenyi Biotec provides products and services worldwide. Visit www.miltenyibiotec.com/local to find your nearest Miltenyi Biotec contact.
Unless otherwise specifically indicated, Miltenyi Biotec products and services are for research use only and not for therapeutic or diagnostic use. MACS® GMP Products are for research use and ex vivo cell culture processing only, and are not intended for human in vivo applications. For regulatory status in the USA, please contact your local representative. MACS GMP Products are manufactured and tested under a quality system certified to ISO 13485 and are in compliance with relevant GMP guidelines. They are designed following the recommendations of USP <1043> on ancillary materials. The CliniMACS® System components, including Reagents, Tubing Sets, Instruments, and PBS/EDTA Buffer, are designed, manufactured and tested under a quality system certified to ISO 13485.In the EU, the CliniMACS System components are available as CE-marked medical devices for their respective intended use, unless otherwise stated. The CliniMACS Reagents and Biotin Conjugates are intended for in vitro use only and are not designated for therapeutic use or direct infusion into patients. The CliniMACS Reagents in combination with the CliniMACS System are intended to separate human cells. Miltenyi Biotec as the manufacturer of the CliniMACS System does not give any recommendations regarding the use of separated cells for therapeutic purposes and does not make any claims regarding a clinical benefit. For the manufacturing and use of target cells in humans the national legislation and regulations – e.g. for the EU the Directive 2004/23/EC (“human tissues and cells”), or the Directive 2002/98/EC (“human blood and blood components”) – must be followed. Thus, any clinical application of the target cells is exclusively within the responsibility of the user of a CliniMACS System. All CliniMACS Product Line solutions described in this leaflet are available for use only under an approved Investigational New Drug (IND) application or Investigational Device Exemption (IDE). CliniMACS MicroBeads are for research use only and not for human therapeutic or diagnostic use. CliniMACS, CliniMACS Prodigy, MACS, MACSQuant, REAfinity and the MACS logo are registered trademarks or trademarks of Miltenyi Biotec GmbH and/or its affiliates in various countries worldwide. Copyright © 2019 Miltenyi Biotec GmbH and/or its affiliates. All rights reserved.
