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Cancer Immunotherapy: The Dawn of Antibody Cocktails

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Human Monoclonal Antibodies

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1904))

Abstract

Since the approval of the first monoclonal antibody (mAb), rituximab, for hematological malignancies, almost 30 additional mAbs have been approved in oncology. Despite remarkable advances, relatively weak responses and resistance to antibody monotherapy remain major open issue. Overcoming resistance might require combinations of drugs blocking both the major target and the emerging secondary target. We review clinically approved combinations of antibodies and either cytotoxic regimens (chemotherapy and irradiation) or kinase inhibitors. Thereafter, we focus on the most promising and currently very active arena that combines mAbs inhibiting immune checkpoints or growth factor receptors. Clinically approved and experimental oligoclonal mixtures of mAbs targeting different antigens (hetero-combinations) or different epitopes of the same antigen (homo-combinations) are described. Effective oligoclonal mixtures of antibodies that mimic the polyclonal immune response will likely become a mainstay of cancer therapy.

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References

  1. Kitano H (2007) The theory of biological robustness and its implication in cancer. Ernst Schering Res Found Workshop 61:69–88

    Article  CAS  Google Scholar 

  2. Amit I, Wides R, Yarden Y (2007) Evolvable signaling networks of receptor tyrosine kinases: relevance of robustness to malignancy and to cancer therapy. Mol Syst Biol 3:151

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hase T, Tanaka H, Suzuki Y, Nakagawa S, Kitano H (2009) Structure of protein interaction networks and their implications on drug design. PLoS Comput Biol 5:e1000550

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Dar AC, Das TK, Shokat KM, Cagan RL (2012) Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486:80–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mancini M, Yarden Y (2015) Mutational and network level mechanisms underlying resistance to anti-cancer kinase inhibitors. Semin Cell Dev Biol 50:164–176

    Article  PubMed  CAS  Google Scholar 

  6. Carvalho S, Levi-Schaffer F, Sela M, Yarden Y (2016) Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti-cancer antibodies: IUPHAR Review 18. Br J Pharmacol 173:1407–1424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kholodenko BN, Hancock JF, Kolch W (2010) Signalling ballet in space and time. Nat Rev Mol Cell Biol 11:414–426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Camidge DR, Pao W, Sequist LV (2014) Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 11:473–481

    Article  CAS  PubMed  Google Scholar 

  9. Garraway LA, Janne PA (2012) Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2:214–226

    Article  CAS  PubMed  Google Scholar 

  10. Piotrowska Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M, Fulton L, Hata AN, Lockerman EL, Kalsy A, Digumarthy S, Muzikansky A, Raponi M, Garcia AR, Mulvey HE, Parks MK, DiCecca RH, Dias-Santagata D, Iafrate AJ, Shaw AT, Allen AR, Engelman JA, Sequist LV (2015) Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov 5:713–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hata AN et al (2016) Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med 22:262–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. DeVita JVT, Lawrence TS, Rosenberg SA, D’ePinho RA, Weinberg RAA (2015) DeVita, Hellman, and Rosenberg’s cancer: principles and practice of oncology. Wolthers Kluwer, Alphen aan den Rijn

    Google Scholar 

  13. Munoz-Garzon V, Rovirosa A, Ramos A (2013) Global radiation oncology waybill. Rep Pract Oncol Radiother 18:321–328

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  15. Hunter T (2007) Treatment for chronic myelogenous leukemia: the long road to imatinib. J Clin Invest 117:2036–2043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Troiani T, Napolitano S, Della Corte CM, Martini G, Martinelli E, Morgillo F, Ciardiello F (2016) Therapeutic value of EGFR inhibition in CRC and NSCLC: 15 years of clinical evidence. ESMO Open 1:e000088

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12:553–563

    Article  CAS  PubMed  Google Scholar 

  18. Treviño SR, Permenter AR, England MJ, Parthasarathy N, Gibbs PH, Waag DM, Chanh TC, Trevin SR (2006) Monoclonal antibodies passively protect BALB/c mice against Burkholderia mallei aerosol challenge. Infect Immun 74:1956–1961

    Article  CAS  Google Scholar 

  19. Stanfield RL, Wilson IA (2009) Antibody molecular structure. In: An Z (ed) Therapeutic monoclonal antibodies: from bench to clinic. John Wiley & Sons, Inc., Hoboken, NJ

    Google Scholar 

  20. Köhler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497

    Article  PubMed  Google Scholar 

  21. Thistlethwaite JRJ, Haag BW, Gaber AO, Stuart JK, Aronson AJ, Mayes JT, Lloyd DM, FP S (1987) The use of OKT3 to treat steroid-resistant renal allograft rejection in patients receiving cyclosporine. Transplant Proc 19:1901–1904

    PubMed  Google Scholar 

  22. Kurosawa N, Yoshioka M, Fujimoto R, Yamagishi F, Isobe M (2012) Rapid production of antigen-specific monoclonal antibodies from a variety of animals. BMC Biol 10:80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reff ME, Hariharan K, Braslawsky G (2002) Future of monoclonal antibodies in the treatment of hematologic malignancies. Cancer Control 9:152–166

    Article  PubMed  Google Scholar 

  24. Morrison SL, Johnson MJ, Herzenberg LA, Oi VT (1984) Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci U S A 81:6851–6855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Faulds D, Sorkin EM (1994) Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischaemic heart disease. Drugs 48:583–598

    Article  CAS  PubMed  Google Scholar 

  26. Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, Halloran P, Neylan J, Wilkinson A, Ekberg H, Gaston R et al (1998) Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med 338:161–165

    Article  CAS  PubMed  Google Scholar 

  27. Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NBM, Hamid M (2012) ScFv antibody: principles and clinical application. Clin Dev Immunol 2012:1–15

    Article  CAS  Google Scholar 

  28. Giusti RM, Shastri KA, Cohen MH, Keegan P, Pazdur R (2007) FDA drug approval summary: panitumumab (Vectibix). Oncologist 12:577–583

    Article  CAS  PubMed  Google Scholar 

  29. Fauvel B, Yasri A (2014) Antibodies directed against receptor tyrosine kinases: current and future strategies to fight cancer. MAbs 6:10–11

    Article  Google Scholar 

  30. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R (1997) IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188–2195

    CAS  PubMed  Google Scholar 

  31. Shak S (1999) Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group. Semin Oncol 26:71–77

    CAS  PubMed  Google Scholar 

  32. Zafir-Lavie I, Michaeli Y, Reiter Y (2007) Novel antibodies as anticancer agents. Oncogene 26:3714–3733

    Article  CAS  PubMed  Google Scholar 

  33. Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443–446

    Article  CAS  PubMed  Google Scholar 

  34. Kim DH, Jung HD, Kim JG, Lee J-J, Yang D-H, Park YH, Do YR, Shin HJ, Kim MK, Hyun MS, Sohn SK (2006) FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood 108:2720–2725

    Article  CAS  PubMed  Google Scholar 

  35. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M (1997) Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype. Blood 90:1109–1114

    CAS  PubMed  Google Scholar 

  36. Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, Chang HM, Borucka E, Lurje G, Sherrod AE, Iqbal S, Groshen S, Lenz HJ (2007) FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 25:3712–3718

    Article  CAS  PubMed  Google Scholar 

  37. Holubec L, Polivka JJ, Safanda M, Karas M, Liska V (2016) The role of cetuximab in the induction of anticancer immune response in colorectal cancer treatment. Anti Cancer Res 36:4421–4426

    CAS  Google Scholar 

  38. Ben-Kasus T, Schechter B, Sela M, Yarden Y (2007) Cancer therapeutic antibodies come of age: targeting minimal residual disease. Mol Oncol 1:42–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, Scanziani E, Botto M, Introna M, Golay J (2003) Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol 171:1581–1587

    Article  PubMed  Google Scholar 

  40. Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, Scanziani E, Botto M, Introna M, Golay J (2006) The role of complement in the therapeutic activity of rituximab in a murine B lymphoma model homing in lymph nodes. Haematologica 91:176–183

    PubMed  Google Scholar 

  41. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391–400

    Article  CAS  PubMed  Google Scholar 

  42. Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF (1993) Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J Cell Biol 121:1121–1132

    Article  CAS  PubMed  Google Scholar 

  43. Cuello M, Ettenberg SA, Clark AS, Keane MM, Posner RH, Nau MM, Dennis PA, Lipkowitz S (2001) Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res 61:4892–4900

    CAS  PubMed  Google Scholar 

  44. Huang SM, Bock JM, Harari PM (1999) Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59:1935–1940

    CAS  PubMed  Google Scholar 

  45. Marches R, Uhr JW (2004) Enhancement of the p27Kip1-mediated antiproliferative effect of trastuzumab (Herceptin) on HER2-overexpressing tumor cells. Int J Cancer 112:492–501

    Article  CAS  PubMed  Google Scholar 

  46. Lange T, Nentwich MF, Lüth M, Yekebas E, Schumacher U (2011) Trastuzumab has anti-metastatic and anti-angiogenic activity in a spontaneous metastasis xenograft model of esophageal adenocarcinoma. Cancer Lett 308:54–61

    Article  CAS  PubMed  Google Scholar 

  47. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM (2005) Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7:301–311

    Article  CAS  PubMed  Google Scholar 

  48. Sunada H, Magun BE, Mendelsohn J, MacLeod CL (1986) Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci U S A 83:3825–3829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Klapper LN, Waterman H, Sela M, Yarden Y (2000) Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2. Cancer Res 60:3384–3388

    CAS  PubMed  Google Scholar 

  50. Klapper LN, Vaisman N, Hurwitz E, Pinkas-Kramarski R, Yarden Y, Sela M (1997) A subclass of tumor-inhibitory monoclonal antibodies to ErbB-2/HER2 blocks crosstalk with growth factor receptors. Oncogene 14:2099–2109

    Article  CAS  PubMed  Google Scholar 

  51. Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, Scher HI, Sliwkowski MX (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2:127–137

    Article  CAS  PubMed  Google Scholar 

  52. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242

    Article  CAS  PubMed  Google Scholar 

  53. Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, Levy R (2000) Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: safety and efficacy of re-treatment. J Clin Oncol 18:3135–3143

    Article  CAS  PubMed  Google Scholar 

  54. Gajria D, Chandarlapaty S (2011) HER2-amplifiedbreast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther 11:263–275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Esteva FJ, Yu D, Hung M-C, Hortobagyi GN (2010) Molecular predictors of response to trastuzumab and lapatinib in breast cancer. Nat Rev Clin Oncol 7:98–107

    Article  CAS  PubMed  Google Scholar 

  56. Pavanello F, Zucca E, Ghielmini M (2017) Rituximab: 13 open questions after 20 years of clinical use. Cancer Treat Rev 53:38–46

    Article  CAS  PubMed  Google Scholar 

  57. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Ramon y Cajal S, Arribas J, Baselga J (2007) Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst 99:628–638

    Article  CAS  PubMed  Google Scholar 

  58. Nagy P, Friedlander E, Tanner M, Kapanen AI, Carraway KL, Isola J, Jovin TM (2005) Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res 65:473–482

    CAS  PubMed  Google Scholar 

  59. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Cote JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P (2006) KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992–3995

    Article  CAS  PubMed  Google Scholar 

  60. Mancini M, Gaborit N, Lindzen M, Salame TM, Dall'Ora M, Sevilla-Sharon M, Abdul-Hai A, Downward J, Yarden Y (2015) Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer. Sci Signal 8:ra53

    Article  PubMed  CAS  Google Scholar 

  61. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852–1857

    Article  CAS  PubMed  Google Scholar 

  62. Shattuck DL, Miller JK, Carraway KL III, Sweeney C (2008) Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res 68:1471–1477

    Article  CAS  PubMed  Google Scholar 

  63. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402

    Article  CAS  PubMed  Google Scholar 

  64. Marshall MJE, Stopforth RJ, Cragg MS (2017) Therapeutic antibodies: what have we learnt from targeting CD20 and where are we going? Front Immunol 8:1245

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Salles G, Barrett M, Foa R, Maurer J, O'Brien S, Valente N, Wenger M, Maloney DG (2017) Rituximab in B-cell hematologic malignancies: a review of 20 years of clinical experience. Adv Ther 34:2232–2273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, Kiyoi H, Kinoshita T, Naoe T (2009) Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance. Blood 113:4885–4893

    Article  CAS  PubMed  Google Scholar 

  67. Czuczman MS, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, Knight J, Starostik P, Deans J, FJ H-I (2008) Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels. Clin Cancer Res 14:1561–1570

    Article  CAS  PubMed  Google Scholar 

  68. Goede V, Klein C, Stilgenbauer S (2015) Obinutuzumab (GA101) for the treatment of chronic lymphocytic leukemia and other B-cell non-Hodgkin’s lymphomas: a glycoengineered type II CD20 antibody. Oncol Res Treat 38:185–192

    Article  CAS  PubMed  Google Scholar 

  69. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    Article  CAS  PubMed  Google Scholar 

  70. Carter PJ (2006) Potent antibody therapeutics by design. Nat Rev Immunol 6:343–357

    Article  CAS  PubMed  Google Scholar 

  71. Dean-Colomb W, Esteva FJ (2008) Her2-positive breast cancer: herceptin and beyond. Eur J Cancer (Oxford) 1990(44):2806–2812

    Article  CAS  Google Scholar 

  72. Vu T, Claret FX (2012) Trastuzumab: updated mechanisms of action and resistance in breast cancer. Front Oncol 18:62–81

    Google Scholar 

  73. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317–328

    Article  CAS  PubMed  Google Scholar 

  74. Schneider MR, Yarden Y (2016) The EGFR-HER2 module: a stem cell approach to understanding a prime target and driver of solid tumors. Oncogene 35:2949–2960

    Article  CAS  PubMed  Google Scholar 

  75. Bronte G, Silvestris N, Castiglia M, Galvano A, Passiglia F, Sortino G, Cicero G, Rolfo C, Peeters M, Bazan V, Fanale D, Giordano A, Russo A (2015) New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS? Oncotarget 6:24780–24796

    PubMed  PubMed Central  Google Scholar 

  76. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127

    Article  CAS  PubMed  Google Scholar 

  77. Spangler JB, Neil JR, Abramovitch S, Yarden Y, White FM, Lauffenburger DA, Wittrup KD (2010) Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling. Proc Natl Acad Sci U S A 107:13252–13257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Park K, Cho EK, Bello M, Ahn M-J, Thongprasert S, Song E-K, Soldatenkova V, Depenbrock H, Puri T, Orlando M (2017) Efficacy and safety of first-line necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin in East Asian patients with stage IV squamous non-small cell lung cancer: a subgroup analysis of the phase 3, open-label, randomized SQUIRE study. Cancer Res Treat 49:937–946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974

    Article  CAS  PubMed  Google Scholar 

  80. Seddon AN, Cuellar S, Haaf CM (2014) The life, death, and attempted rebirth of bevacizumab in breast cancer. J Oncol Pharm Pract 20:433–444

    Article  PubMed  CAS  Google Scholar 

  81. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360

    Article  CAS  PubMed  Google Scholar 

  82. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science (New York, NY) 271:1734–1736

    Article  CAS  Google Scholar 

  83. Chambers CA, Kuhns MS, Egen JG, Allison JP (2001) CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 19:565–594

    Article  CAS  PubMed  Google Scholar 

  84. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain J-F, Testori A, Grob J-J, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen T-T, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526

    Article  CAS  PubMed  Google Scholar 

  85. Postow MA, Sidlow R, Hellmann MD (2018) Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 378:158–168

    Article  PubMed  Google Scholar 

  86. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800

    Article  CAS  PubMed  Google Scholar 

  87. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 99:12293–12297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol 32:1020–1030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Brahmer J et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Motzer RJ et al (2015) Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm M-O, Bracarda S, Arranz JA, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322

    Article  CAS  PubMed  Google Scholar 

  92. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, Rodig SJ, Chapuy B, Ligon AH, Zhu L, Grosso JF, Kim SY, Timmerman JM, Shipp MA, Armand P (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311–319

    Article  PubMed  CAS  Google Scholar 

  93. Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science (New York, NY) 359:1350–1355

    Article  CAS  Google Scholar 

  94. Kahl B (2008) Chemotherapy combinations with monoclonal antibodies in non-Hodgkin’s lymphoma. Semin Hematol 45:90–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  CAS  PubMed  Google Scholar 

  96. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567–578

    Article  CAS  PubMed  Google Scholar 

  97. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R, Bartlett NL, Cheson BD, de Vos S, Forero-Torres A, Moskowitz CH, Connors JM, Engert A, Larsen EK, Kennedy DA, Sievers EL, Chen R (2012) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30:2183–2189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A (2012) Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 30:2190–2196

    Article  CAS  PubMed  Google Scholar 

  99. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367:1783–1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhong W-Z, Zhou Q, Wu Y-L (2017) The resistance mechanisms and treatment strategies for EGFR-mutant advanced non-small-cell lung cancer. Oncotarget 8:71358–71370

    PubMed  PubMed Central  Google Scholar 

  101. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792

    Article  CAS  PubMed  Google Scholar 

  102. Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W (2007) MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104:20932–20937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, Michel K, Peifer M, Mermel C, Girard L, Peyton M, Gazdar AF, Minna JD, Garraway LA, Kashkar H, Pao W, Meyerson M, Thomas RK (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Huang S, Armstrong EA, Benavente S, Chinnaiyan P, Harari PM (2004) Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 64:5355–5362

    Article  CAS  PubMed  Google Scholar 

  105. El Guerrab A, Bamdad M, Kwiatkowski F, Bignon Y-J, Penault-Llorca F, Aubel C (2016) Anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors as combination therapy for triple-negative breast cancer. Oncotarget 7:73618–73637

    Article  PubMed  PubMed Central  Google Scholar 

  106. Mancini M, Gal H, Gaborit N, Mazzeo L, Romaniello D, Salame TM, Lindzen M, Mahlknecht G, Enuka Y, Burton DG, Roth L, Noronha A, Marrocco I, Adreka D, Altstadter RE, Bousquet E, Downward J, Maraver A, Krizhanovsky V, Yarden Y (2017) An oligoclonal antibody durably overcomes resistance of lung cancer to third-generation EGFR inhibitors. EMBO Mol Med 10:294–308

    Article  PubMed Central  CAS  Google Scholar 

  107. Spigel DR, Edelman MJ, O'Byrne K, Paz-Ares L, Mocci S, Phan S, Shames DS, Smith D, Yu W, Paton VE, Mok T (2017) Results from the phase III randomized trial of onartuzumab plus erlotinib versus erlotinib in previously treated stage IIIB or IV non-small-cell lung cancer: METLung. J Clin Oncol 35:412–420

    Article  CAS  PubMed  Google Scholar 

  108. Herbst RS, O'Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, Melnyk O, Ramies D, Lin M, Sandler A (2007) Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non small-cell lung cancer. J Clin Oncol 25:4743–4750

    Article  CAS  PubMed  Google Scholar 

  109. Rosell R et al (2017) Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med 5:435–444

    Article  CAS  PubMed  Google Scholar 

  110. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255–6263

    Article  CAS  PubMed  Google Scholar 

  111. Ahn ER, Vogel CL (2012) Dual HER2-targeted approaches in HER2-positive breast cancer. Breast Cancer Res Treat 131:371–383

    Article  PubMed  Google Scholar 

  112. Mosesson Y, Mills GB, Yarden Y (2008) Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 8:835–850

    Article  CAS  PubMed  Google Scholar 

  113. Abella JV, Park M (2009) Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am J Physiol Endocrinol Metab 296:E973–E984

    Article  CAS  PubMed  Google Scholar 

  114. Fan Z, Masui H, Altas I, Mendelsohn J (1993) Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 53:4322–4328

    CAS  PubMed  Google Scholar 

  115. Drebin JA, Link VC, Greene MI (1988) Monoclonal antibodies reactive with distinct domains of the neu oncogene-encoded p185 molecule exert synergistic anti-tumor effects in vivo. Oncogene 2:273–277

    CAS  PubMed  Google Scholar 

  116. Spiridon CI, Ghetie MA, Uhr J, Marches R, Li JL, Shen GL, Vitetta ES (2002) Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. Clin Cancer Res 8:1720–1730

    CAS  PubMed  Google Scholar 

  117. Kasprzyk PG, Song SU, Di Fiore PP, King CR (1992) Therapy of an animal model of human gastric cancer using a combination of anti-erbB-2 monoclonal antibodies. Cancer Res 52:2771–2776

    CAS  PubMed  Google Scholar 

  118. Ben-Kasus T, Schechter B, Lavi S, Yarden Y, Sela M (2009) Persistent elimination of ErbB-2/HER2-overexpressing tumors using combinations of monoclonal antibodies: relevance of receptor endocytosis. Proc Natl Acad Sci U S A 106:3294–3299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, Bacus SS, Sela M, Yarden Y (2005) Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc Natl Acad Sci U S A 102:1915–1920

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429–440

    Article  CAS  PubMed  Google Scholar 

  121. Nahta R, Hung MC, Esteva FJ (2004) The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 64:2343–2346

    Article  CAS  PubMed  Google Scholar 

  122. Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M (2009) Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res 69:9330–9336

    Article  CAS  PubMed  Google Scholar 

  123. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J, Group CS (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Swain SM, Kim S-B, Cortes J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero J-M, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J (2013) Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 14:461–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, Moliterni A, Vazquez F, Byakhov MJ, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Magazzu D, Heinzmann D, Steinseifer J, Valagussa P, Baselga J (2014) Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol 15:640–647

    Article  CAS  PubMed  Google Scholar 

  126. von Minckwitz G et al (2017) Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122–131

    Article  Google Scholar 

  127. Jaramillo ML, Leon Z, Grothe S, Paul-Roc B, Abulrob A, O'Connor McCourt M (2006) Effect of the anti-receptor ligand-blocking 225 monoclonal antibody on EGF receptor endocytosis and sorting. Exp Cell Res 312:2778–2790

    Article  CAS  PubMed  Google Scholar 

  128. Pedersen MW, Jacobsen HJ, Koefoed K, Hey A, Pyke C, Haurum JS, Kragh M (2010) Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. Cancer Res 70:588–597

    Article  CAS  PubMed  Google Scholar 

  129. Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Rosello S, Tops BB, van der Post RS, Argiles G, Skartved NJ, Hansen UH, Hald R, Pedersen MW, Kragh M, Horak ID, Braun S, Van Cutsem E, Tolcher AW, Tabernero J (2015) Safety and activity of the first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov 5:598–609

    Article  CAS  PubMed  Google Scholar 

  130. Montagut C et al (2018) Efficacy of Sym004 in patients with metastatic colorectal cancer with acquired resistance to anti-EGFR therapy and molecularly selected by circulating tumor DNA analyses: a phase 2 randomized clinical trial. JAMA Oncol 4:e175245

    Article  PubMed  PubMed Central  Google Scholar 

  131. Vigna E, Comoglio PM (2014) Targeting the oncogenic Met receptor by antibodies and gene therapy. Oncogene 34:1883–1889

    Article  PubMed  CAS  Google Scholar 

  132. Kawakami H, Okamoto I, Arao T, Okamoto W, Matsumoto K, Taniguchi H, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K, Yamada Y (2013) MET amplification as a potential therapeutic target in gastric cancer. Oncotarget 4:9–17

    Article  PubMed  Google Scholar 

  133. Dimou A, Non L, Chae YK, Tester WJ, Syrigos KN (2014) MET gene copy number predicts worse overall survival in patients with non-small cell lung cancer (NSCLC); a systematic review and meta-analysis. PLoS One 9:e107677

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Grandal MM, Havrylov S, Poulsen TT, Koefoed K, Dahlman A, Galler GR, Conrotto P, Collins S, Eriksen KW, Kaufman D, Woude GFV, Jacobsen HJ, Horak ID, Kragh M, Lantto J, Bouquin T, Park M, Pedersen MW (2017) Simultaneous targeting of two distinct epitopes on MET effectively inhibits MET- and HGF-driven tumor growth by multiple mechanisms. Mol Cancer Ther 16:2780–2791

    Article  CAS  PubMed  Google Scholar 

  135. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J, Rosen N (2011) AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19:58–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, Gondi V, Hsu KT, Harari PM (2008) Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27:3944–3956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Iida M, Bahrar H, Brand TM, Pearson HE, Coan JP, Orbuch RA, Flanigan BG, Swick AD, Prabakaran PJ, Lantto J, Horak ID, Kragh M, Salgia R, Kimple RJ, DL W (2016) Targeting the HER family with pan-HER effectively overcomes resistance to cetuximab. Mol Cancer Ther 15:2175–2186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Iida M, Brand TM, Starr MM, Huppert EJ, Luthar N, Bahrar H, Coan JP, Pearson HE, Salgia R, Wheeler DL (2014) Overcoming acquired resistance to cetuximab by dual targeting HER family receptors with antibody-based therapy. Mol Cancer 13:242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Gaborit N, Lindzen M, Yarden Y (2016) Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3. Hum Vaccin Immunother 12:576–592

    Article  PubMed  Google Scholar 

  140. Mukai H, Saeki T, Aogi K, Naito Y, Matsubara N, Shigekawa T, Ueda S, Takashima S, Hara F, Yamashita T, Ohwada S, Sasaki Y (2016) Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. Cancer Sci 107:1465–1470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wei SC, Levine JH, Cogdill AP, Zhao Y, Anang N-AAS, Andrews MC, Sharma P, Wang J, Wargo JA, Pe'er D, Allison JP (2017) Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170:1120–1133.e17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369:122–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006–2017

    Article  PubMed  PubMed Central  Google Scholar 

  144. Hellmann MD, Ciuleanu T-E, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 378:2093–2104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Larkin J et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J-J, Cowey CL, Lao CD, Chesney J, Robert C, Grossmann K, McDermott D, Walker D, Bhore R, Larkin J, MA P (2017) efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol 35:3807–3814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Krishnamurthy A, Jimeno A (2018) Bispecific antibodies for cancer therapy: a review. Pharmacol Ther 185:122–134

    Article  CAS  PubMed  Google Scholar 

  148. Wu J, Fu J, Zhang M, Liu D (2015) Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol 8:104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgments

Our laboratory has been supported by the European Research Council, the Israel Science Foundation, the Israel Cancer Research Fund, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. I.M. and D.R. received the Sergio Lombroso Fellowship for postdoctoral cancer research. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. Our studies were performed in the Marvin Tanner Laboratory for Research on Cancer.

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  1. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Ilaria Marrocco, Donatella Romaniello & Yosef Yarden

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  1. Ilaria Marrocco
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  2. Donatella Romaniello
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Correspondence to Yosef Yarden .

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  1. Department of Pathology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel

    Michael Steinitz

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Marrocco, I., Romaniello, D., Yarden, Y. (2019). Cancer Immunotherapy: The Dawn of Antibody Cocktails. In: Steinitz, M. (eds) Human Monoclonal Antibodies. Methods in Molecular Biology, vol 1904. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8958-4_2

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