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Natural Killer Cells pp 333–346Cite as

Generation of BiKEs and TriKEs to Improve NK Cell-Mediated Targeting of Tumor Cells

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 1441))

Abstract

Cancer immunotherapies have gained significant momentum over the past decade, particularly with the advent of checkpoint inhibitors and CAR T-cells. While the latter personalized targeted immunotherapy has revolutionized the field, a need for off-the-shelf therapies remains. The ability of NK cells to quickly lyse antibody-coated tumors and potently secrete cytokines without prior priming has made NK cells ideal candidates for antigen-specific immunotherapy. NK cells have been targeted to tumors through two main strategies: mono-specific antibodies and bi/tri-specific antibodies. Mono-specific antibodies drive NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) of tumor cells. Bi/tri-specific antibodies drive re-directed lysis of tumor cells through binding of a tumor antigen and direct binding and crosslinking of the CD16 receptor on NK cells, thus bypassing the need for binding of the Fc portion of mono-specific antibodies. This chapter focuses on the generation of bi- and tri-specific killer engagers (BiKEs and TriKEs) meant to target NK cells to tumors. BiKEs and TriKEs are smaller molecules composed of 2–3 variable portions of antibodies with different specificities, and represent a novel and more versatile strategy compared to traditional bi- and tri-specific antibody platforms.

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References

  1. Masters GA, Krilov L, Bailey HH et al (2015) Clinical cancer advances 2015: Annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol 33:786–809

    Article  PubMed  Google Scholar 

  2. Caruana I, Diaconu I, Dotti G (2014) From monoclonal antibodies to chimeric antigen receptors for the treatment of human malignancies. Semin Oncol 41:661–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hermanson DL, Kaufman DS (2015) Utilizing chimeric antigen receptors to direct natural killer cell activity. Front Immunol 6:195

    Article  PubMed  PubMed Central  Google Scholar 

  4. Glienke W, Esser R, Priesner C et al (2015) Advantages and applications of CAR-expressing natural killer cells. Front Pharmacol 6:21

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vivier E, Raulet DH, Moretta A et al (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Velardi A (2012) Natural killer cell alloreactivity 10 years later. Curr Opin Hematol 19:421–426

    Article  CAS  PubMed  Google Scholar 

  7. Anegon I, Cuturi MC, Trinchieri G et al (1988) Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells. J Exp Med 167:452–472

    Article  CAS  PubMed  Google Scholar 

  8. Ravetch JV, Bolland S (2001) IgG Fc receptors. Annu Rev Immunol 19:275–290

    Article  CAS  PubMed  Google Scholar 

  9. Selvaraj P, Carpen O, Hibbs ML et al (1989) Natural killer cell and granulocyte Fc gamma receptor III (CD16) differ in membrane anchor and signal transduction. J Immunol 143:3283–3288

    CAS  PubMed  Google Scholar 

  10. Perussia B, Ravetch JV (1991) Fc gamma RIII (CD16) on human macrophages is a functional product of the Fc gamma RIII-2 gene. Eur J Immunol 21:425–429

    Article  CAS  PubMed  Google Scholar 

  11. Klaassen RJ, Ouwehand WH, Huizinga TW et al (1990) The Fc-receptor III of cultured human monocytes. Structural similarity with FcRIII of natural killer cells and role in the extracellular lysis of sensitized erythrocytes. J Immunol 144:599–606

    CAS  PubMed  Google Scholar 

  12. Nishikiori N, Koyama M, Kikuchi T et al (1993) Membrane-spanning Fc gamma receptor III isoform expressed on human placental trophoblasts. Am J Reprod Immunol 29:17–25

    Article  CAS  PubMed  Google Scholar 

  13. Ravetch JV, Perussia B (1989) Alternative membrane forms of Fc gamma RIII(CD16) on human natural killer cells and neutrophils. Cell type-specific expression of two genes that differ in single nucleotide substitutions. J Exp Med 170:481–497

    Article  CAS  PubMed  Google Scholar 

  14. Lanier LL, Ruitenberg JJ, Phillips JH (1988) Functional and biochemical analysis of CD16 antigen on natural killer cells and granulocytes. J Immunol 141:3478–3485

    CAS  PubMed  Google Scholar 

  15. Wirthmueller U, Kurosaki T, Murakami MS et al (1992) Signal transduction by Fc gamma RIII (CD16) is mediated through the gamma chain. J Exp Med 175:1381–1390

    Article  CAS  PubMed  Google Scholar 

  16. Cooper MA, Fehniger TA, Caligiuri MA (2001) The biology of human natural killer-cell subsets. Trends Immunol 22:633–640

    Article  CAS  PubMed  Google Scholar 

  17. Beziat V, Duffy D, Quoc SN et al (2011) CD56brightCD16+ NK cells: a functional intermediate stage of NK cell differentiation. J Immunol 186:6753–6761

    Article  CAS  PubMed  Google Scholar 

  18. Vivier E, Nunes JA, Vely F (2004) Natural killer cell signaling pathways. Science 306:1517–1519

    Article  CAS  PubMed  Google Scholar 

  19. Vivier E, Morin P, O’Brien C et al (1991) Tyrosine phosphorylation of the Fc gamma RIII(CD16): zeta complex in human natural killer cells. Induction by antibody-dependent cytotoxicity but not by natural killing. J Immunol 146:206–210

    CAS  PubMed  Google Scholar 

  20. Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47

    Article  CAS  PubMed  Google Scholar 

  21. Bryceson YT, Ljunggren HG, Long EO (2009) Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114:2657–2666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shore SL, Nahmias AJ, Starr SE et al (1974) Detection of cell-dependent cytotoxic antibody to cells infected with herpes simplex virus. Nature 251:350–352

    Article  CAS  PubMed  Google Scholar 

  23. Laszlo A, Petri I, Ilyes M (1986) Antibody dependent cellular cytotoxicity (ADCC)-reaction and an in vitro steroid sensitivity test of peripheral lymphocytes in children with malignant haematological and autoimmune diseases. Acta Paediatr Hung 27:23–29

    CAS  PubMed  Google Scholar 

  24. Natsume A, Niwa R, Satoh M (2009) Improving effector functions of antibodies for cancer treatment: Enhancing ADCC and CDC. Drug Des Devel Ther 3:7–16

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Albertini MR, Hank JA, Sondel PM (2005) Native and genetically engineered anti-disialoganglioside monoclonal antibody treatment of melanoma. Cancer Chemother Biol Response Modif 22:789–797

    Article  CAS  PubMed  Google Scholar 

  26. Garcia-Foncillas J, Diaz-Rubio E (2010) Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome. Clin Trans Oncol 12:533–542

    Article  CAS  Google Scholar 

  27. Garnock-Jones KP, Keating GM, Scott LJ (2010) Trastuzumab: A review of its use as adjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. Drugs 70:215–239

    Article  CAS  PubMed  Google Scholar 

  28. Navid F, Santana VM, Barfield RC (2010) Anti-GD2 antibody therapy for GD2-expressing tumors. Curr Cancer Drug Targets 10:200–209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Winter MC, Hancock BW (2009) Ten years of rituximab in NHL. Expert Opin Drug Saf 8:223–235

    Article  CAS  PubMed  Google Scholar 

  30. Congy-Jolivet N, Bolzec A, Ternant D et al (2008) Fc gamma RIIIa expression is not increased on natural killer cells expressing the Fc gamma RIIIa-158V allotype. Cancer Res 68:976–980

    Article  CAS  PubMed  Google Scholar 

  31. Moore GL, Bautista C, Pong E et al (2011) A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens. MAbs 3:546–557

    Article  PubMed  PubMed Central  Google Scholar 

  32. Preithner S, Elm S, Lippold S et al (2006) High concentrations of therapeutic IgG1 antibodies are needed to compensate for inhibition of antibody-dependent cellular cytotoxicity by excess endogenous immunoglobulin G. Mol Immunol 43:1183–1193

    Article  CAS  PubMed  Google Scholar 

  33. Baselga J, Albanell J (2001) Mechanism of action of anti-HER2 monoclonal antibodies. Ann Oncol 12(Suppl 1):S35–S41

    Article  PubMed  Google Scholar 

  34. Berinstein NL, Grillo-Lopez AJ, White CA et al (1998) Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol 9:995–1001

    Article  CAS  PubMed  Google Scholar 

  35. Holliger P, Hudson PJ (2005) Engineered antibody fragments and the rise of single domains. Nat Biotechnol 23:1126–1136

    Article  CAS  PubMed  Google Scholar 

  36. Chames P, Van Regenmortel M, Weiss E et al (2009) Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol 157:220–233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scott AM, Wolchok JD, Old LJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12:278–287

    Article  CAS  PubMed  Google Scholar 

  38. Ferrini S, Cambiaggi A, Cantoni C et al (1992) Targeting of T or NK lymphocytes against tumor cells by bispecific monoclonal antibodies: role of different triggering molecules. Int J Cancer 7:15–18

    CAS  Google Scholar 

  39. Glorius P, Baerenwaldt A, Kellner C et al (2013) The novel tribody [(CD20)(2)xCD16] efficiently triggers effector cell-mediated lysis of malignant B cells. Leukemia 27:190–201

    Article  CAS  PubMed  Google Scholar 

  40. Kipriyanov SM, Cochlovius B, Schafer HJ et al (2002) Synergistic antitumor effect of bispecific CD19 x CD3 and CD19 x CD16 diabodies in a preclinical model of non-Hodgkin’s lymphoma. J Immunol 169:137–144

    Article  CAS  PubMed  Google Scholar 

  41. Kellner C, Bruenke J, Stieglmaier J et al (2008) A novel CD19-directed recombinant bispecific antibody derivative with enhanced immune effector functions for human leukemic cells. J Immunother 31:871–884

    Article  CAS  PubMed  Google Scholar 

  42. Kellner C, Bruenke J, Horner H et al (2011) Heterodimeric bispecific antibody-derivatives against CD19 and CD16 induce effective antibody-dependent cellular cytotoxicity against B-lymphoid tumor cells. Cancer Lett 303:128–139

    Article  CAS  PubMed  Google Scholar 

  43. Portner LM, Schonberg K, Hejazi M et al (2012) T and NK cells of B cell NHL patients exert cytotoxicity against lymphoma cells following binding of bispecific tetravalent antibody CD19 x CD3 or CD19 x CD16. Cancer Immunol Immunother 61:1869–1875

    Article  PubMed  Google Scholar 

  44. Bruenke J, Barbin K, Kunert S et al (2005) Effective lysis of lymphoma cells with a stabilised bispecific single-chain Fv antibody against CD19 and FcgammaRIII (CD16). Br J Haematol 130:218–228

    Article  CAS  PubMed  Google Scholar 

  45. Johnson S, Burke S, Huang L et al (2010) Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J Mol Biol 399:436–449

    Article  CAS  PubMed  Google Scholar 

  46. Schlenzka J, Moehler TM, Kipriyanov SM et al (2004) Combined effect of recombinant CD19 x CD16 diabody and thalidomide in a preclinical model of human B cell lymphoma. Anticancer Drugs 15:915–919

    Article  CAS  PubMed  Google Scholar 

  47. Schubert I, Kellner C, Stein C et al (2012) A recombinant triplebody with specificity for CD19 and HLA-DR mediates preferential binding to antigen double-positive cells by dual-targeting. MAbs 4:45–56

    Article  PubMed  PubMed Central  Google Scholar 

  48. Schubert I, Kellner C, Stein C et al (2011) A single-chain triplebody with specificity for CD19 and CD33 mediates effective lysis of mixed lineage leukemia cells by dual targeting. MAbs 3:21–30

    Article  PubMed  PubMed Central  Google Scholar 

  49. Silla LM, Chen J, Zhong RK et al (1995) Potentiation of lysis of leukaemia cells by a bispecific antibody to CD33 and CD16 (Fc gamma RIII) expressed by human natural killer (NK) cells. Br J Haematol 89:712–718

    Article  CAS  PubMed  Google Scholar 

  50. Singer H, Kellner C, Lanig H et al (2010) Effective elimination of acute myeloid leukemic cells by recombinant bispecific antibody derivatives directed against CD33 and CD16. J Immunother 33:599–608

    Article  CAS  PubMed  Google Scholar 

  51. Kugler M, Stein C, Kellner C et al (2010) A recombinant trispecific single-chain Fv derivative directed against CD123 and CD33 mediates effective elimination of acute myeloid leukaemia cells by dual targeting. Br J Haematol 150:574–586

    Article  PubMed  Google Scholar 

  52. Bruenke J, Fischer B, Barbin K et al (2004) A recombinant bispecific single-chain Fv antibody against HLA class II and FcgammaRIII (CD16) triggers effective lysis of lymphoma cells. Br J Haematol 125:167–179

    Article  CAS  PubMed  Google Scholar 

  53. Hombach A, Jung W, Pohl C et al (1993) A CD16/CD30 bispecific monoclonal antibody induces lysis of Hodgkin’s cells by unstimulated natural killer cells in vitro and in vivo. Int J Cancer 55:830–836

    Article  CAS  PubMed  Google Scholar 

  54. Renner C, Pfreundschuh M (1995) Treatment of heterotransplanted Hodgkin’s tumors in SCID mice by a combination of human NK or T cells and bispecific antibodies. J Hematother 4:447–451

    Article  CAS  PubMed  Google Scholar 

  55. Sahin U, Kraft-Bauer S, Ohnesorge S et al (1996) Interleukin-12 increases bispecific-antibody-mediated natural killer cell cytotoxicity against human tumors. Cancer Immunol Immunother 42:9–14

    Article  CAS  PubMed  Google Scholar 

  56. Renner C, Hartmann F, Pfreundschuh M (1997) Treatment of refractory Hodgkin’s disease with an anti-CD16/CD30 bispecific antibody. Cancer Immunol Immunother 45:184–186

    Article  CAS  PubMed  Google Scholar 

  57. Hartmann F, Renner C, Jung W et al (1997) Treatment of refractory Hodgkin’s disease with an anti-CD16/CD30 bispecific antibody. Blood 89:2042–2047

    CAS  PubMed  Google Scholar 

  58. Hartmann F, Renner C, Jung W et al (1998) Anti-CD16/CD30 bispecific antibodies as possible treatment for refractory Hodgkin’s disease. Leuk Lymphoma 31:385–392

    Article  CAS  PubMed  Google Scholar 

  59. da Costa L, Renner C, Hartmann F et al (2000) Immune recruitment by bispecific antibodies for the treatment of Hodgkin disease. Cancer Chemother Pharmacol 46(Suppl):S33–S36

    Article  PubMed  Google Scholar 

  60. Renner C, Hartmann F, Jung W et al (2000) Initiation of humoral and cellular immune responses in patients with refractory Hodgkin’s disease by treatment with an anti-CD16/CD30 bispecific antibody. Cancer Immunol Immunother 49:173–180

    Article  CAS  PubMed  Google Scholar 

  61. Reiners KS, Kessler J, Sauer M et al (2013) Rescue of impaired NK cell activity in Hodgkin lymphoma with bispecific antibodies in vitro and in patients. Mol Ther 21:895–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Arndt MA, Krauss J, Kipriyanov SM et al (1999) A bispecific diabody that mediates natural killer cell cytotoxicity against xenotransplantated human Hodgkin’s tumors. Blood 94:2562–2568

    CAS  PubMed  Google Scholar 

  63. Ferrini S, Cambiaggi A, Sforzini S et al (1993) Use of anti-CD3 and anti-CD16 bispecific monoclonal antibodies for the targeting of T and NK cells against tumor cells. Cancer Detect Prev 17:295–300

    CAS  PubMed  Google Scholar 

  64. Elsasser D, Stadick H, Stark S et al (1999) Preclinical studies combining bispecific antibodies with cytokine-stimulated effector cells for immunotherapy of renal cell carcinoma. Anticancer Res 19:1525–1528

    CAS  PubMed  Google Scholar 

  65. Weiner LM, Clark JI, Davey M et al (1995) Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. Cancer Res 55:4586–4593

    CAS  PubMed  Google Scholar 

  66. Weiner LM, Clark JI, Ring DB et al (1995) Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. J Hematother 4:453–456

    Article  CAS  PubMed  Google Scholar 

  67. Shahied LS, Tang Y, Alpaugh RK et al (2004) Bispecific minibodies targeting HER2/neu and CD16 exhibit improved tumor lysis when placed in a divalent tumor antigen binding format. J Biol Chem 279:53907–53914

    Article  CAS  PubMed  Google Scholar 

  68. Xie Z, Shi M, Feng J et al (2003) A trivalent anti-erbB2/anti-CD16 bispecific antibody retargeting NK cells against human breast cancer cells. Biochem Biophys Res Commun 311:307–312

    Article  CAS  PubMed  Google Scholar 

  69. Stockmeyer B, Valerius T, Repp R et al (1997) Preclinical studies with Fc(gamma)R bispecific antibodies and granulocyte colony-stimulating factor-primed neutrophils as effector cells against HER-2/neu overexpressing breast cancer. Cancer Res 57:696–701

    CAS  PubMed  Google Scholar 

  70. Weiner LM, Holmes M, Adams GP et al (1993) A human tumor xenograft model of therapy with a bispecific monoclonal antibody targeting c-erbB-2 and CD16. Cancer Res 53:94–100

    CAS  PubMed  Google Scholar 

  71. Weiner LM, Holmes M, Richeson A et al (1993) Binding and cytotoxicity characteristics of the bispecific murine monoclonal antibody 2B1. J Immunol 151:2877–2886

    CAS  PubMed  Google Scholar 

  72. Ferrini S, Prigione I, Miotti S et al (1991) Bispecific monoclonal antibodies directed to CD16 and to a tumor-associated antigen induce target-cell lysis by resting NK cells and by a subset of NK clones. Int J Cancer 48:227–233

    Article  CAS  PubMed  Google Scholar 

  73. Gleason MK, Verneris MR, Todhunter DA et al (2012) Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production. Mol Cancer Ther 11:2674–2684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wiernik A, Foley B, Zhang B et al (2013) Targeting Natural Killer Cells to Acute Myeloid Leukemia In Vitro with a CD16 x 33 Bispecific Killer Cell Engager and ADAM17 Inhibition. Clin Cancer Res 19:3844–3855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gleason MK, Ross JA, Warlick ED et al (2014) CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123:3016–3026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Vallera DA, Zhang B, Gleason MK et al (2013) Heterodimeric Bispecific Single-Chain Variable-Fragment Antibodies Against EpCAM and CD16 Induce Effective Antibody-Dependent Cellular Cytotoxicity Against Human Carcinoma Cells. Cancer Biother Radiopharm 28(4):274–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chen X, Zaro JL, Shen WC (2013) Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev 65:1357–1369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Huston JS, Levinson D, Mudgett-Hunter M et al (1988) Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci U S A 85:5879–5883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Whitlow M, Bell BA, Feng SL et al (1993) An improved linker for single-chain Fv with reduced aggregation and enhanced proteolytic stability. Protein Eng 6:989–995

    Article  CAS  PubMed  Google Scholar 

  80. Jager V, Bussow K, Wagner A et al (2013) High level transient production of recombinant antibodies and antibody fusion proteins in HEK293 cells. BMC Biotechnol 13:52

    Article  PubMed  PubMed Central  Google Scholar 

  81. Sorensen HP, Mortensen KK (2005) Advanced genetic strategies for recombinant protein expression in Escherichia coli. J Biotechnol 115:113–128

    Article  CAS  PubMed  Google Scholar 

  82. Nakayama H, Shimamoto N (2014) Modern and simple construction of plasmid: saving time and cost. J Microbiol 52:891–897

    Article  CAS  PubMed  Google Scholar 

  83. Gibson DG, Benders GA, Andrews-Pfannkoch C et al (2008) Complete chemical synthesis, assembly, and cloning of a Mycoplasma genitalium genome. Science 319:1215–1220

    Article  CAS  PubMed  Google Scholar 

  84. Gopal GJ, Kumar A (2013) Strategies for the production of recombinant protein in Escherichia coli. Protein J 32:419–425

    Article  CAS  PubMed  Google Scholar 

  85. Burgess RR (2009) Refolding solubilized inclusion body proteins. Methods Enzymol 463:259–282

    Article  CAS  PubMed  Google Scholar 

  86. Lichty JJ, Malecki JL, Agnew HD et al (2005) Comparison of affinity tags for protein purification. Protein Expr Purif 41:98–105

    Article  CAS  PubMed  Google Scholar 

  87. Kim JY, Kim YG, Lee GM (2012) CHO cells in biotechnology for production of recombinant proteins: current state and further potential. Appl Microbiol Biotechnol 93:917–930

    Article  CAS  PubMed  Google Scholar 

  88. Reff ME, Carner K, Chambers KS et al (1994) Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 83:435–445

    CAS  PubMed  Google Scholar 

  89. Harrison D, Phillips JH, Lanier LL (1991) Involvement of a metalloprotease in spontaneous and phorbol ester-induced release of natural killer cell-associated Fc gamma RIII (CD16-II). J Immunol 147:3459–3465

    CAS  PubMed  Google Scholar 

  90. Borrego F, Lopez-Beltran A, Pena J et al (1994) Downregulation of Fc gamma receptor IIIA alpha (CD16-II) on natural killer cells induced by anti-CD16 mAb is independent of protein tyrosine kinases and protein kinase C. Cell Immunol 158:208–217

    Article  CAS  PubMed  Google Scholar 

  91. Grzywacz B, Kataria N, Verneris MR (2007) CD56(dim)CD16(+) NK cells downregulate CD16 following target cell induced activation of matrix metalloproteinases. Leukemia 21:356–359, author reply 359

    Article  CAS  PubMed  Google Scholar 

  92. Liu Q, Sun Y, Rihn S et al (2009) Matrix metalloprotease inhibitors restore impaired NK cell-mediated antibody-dependent cellular cytotoxicity in human immunodeficiency virus type 1 infection. J Virol 83:8705–8712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Edsparr K, Speetjens FM, Mulder-Stapel A et al (2010) Effects of IL-2 on MMP expression in freshly isolated human NK cells and the IL-2-independent NK cell line YT. J Immunother 33:475–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Romee R, Foley B, Lenvik T et al (2013) NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 121:3599–3608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhou Q, Gil-Krzewska A, Peruzzi G et al (2013) Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy. Clin Exp Immunol 173:131–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Romee R, Leong JW, Fehniger TA (2014) Utilizing cytokines to function-enable human NK cells for the immunotherapy of cancer. Scientifica (Cairo) 2014:205796

    PubMed Central  Google Scholar 

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    Authors and Affiliations

    1. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA

      Martin Felices, Todd R. Lenvik, Zachary B. Davis & Jeffrey S. Miller

    2. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

      Martin Felices, Todd R. Lenvik, Zachary B. Davis, Jeffrey S. Miller & Daniel A. Vallera

    3. Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, MN, USA

      Daniel A. Vallera

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    1. Martin Felices
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    2. Todd R. Lenvik
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    3. Zachary B. Davis
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    Correspondence to Jeffrey S. Miller .

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    1. Division of Pediatrics, M.D. Anderson Cancer Center, Houston, Texas, USA

      Srinivas S. Somanchi

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    Felices, M., Lenvik, T.R., Davis, Z.B., Miller, J.S., Vallera, D.A. (2016). Generation of BiKEs and TriKEs to Improve NK Cell-Mediated Targeting of Tumor Cells. In: Somanchi, S. (eds) Natural Killer Cells. Methods in Molecular Biology, vol 1441. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3684-7_28

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    • DOI: https://doi.org/10.1007/978-1-4939-3684-7_28

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