Complement System: a Neglected Pathway in Immunotherapy

  • Anne Bordron
  • Cristina Bagacean
  • Adrian Tempescul
  • Christian Berthou
  • Eléonore Bettacchioli
  • Sophie Hillion
  • Yves RenaudineauEmail author


Approved for the treatment of autoimmune diseases, hematological malignancies, and solid cancers, several monoclonal antibodies (mAb) make use of complement in their mechanism of action. Such an assessment is based on comprehensive investigations that used mouse models, in vitro studies, and analyses from patients at initiation (basal level to highlight deficiencies) and after treatment initiation (mAb impact on complement), which have further provided key insights into the importance of the complement activation and/or complement deficiencies in mAb activity. Accordingly, new approaches can now be developed with the final objective of increasing the clinical efficacy of mAb. These improvements include (i) the concurrent administration of fresh frozen plasma during mAb therapy; (ii) mAb modifications such as immunoglobulin G subclass switching, Fc mutation, or IgG hexamerization to improve the fixation and activation of C1q; (iii) optimization of the target recognition to induce a higher complement-dependent cytotoxicity (CDC) and/or complement-dependant cellular cytotoxicity (CDCC); and (iv) the control of soluble and cellular complement inhibitors.


Monoclonal antibody Complement Autoimmunity cancer 



We are thankful to Servier Medical for providing free art for the figures, and Genevieve Michel for secretarial help.


This study was supported by the “Ligue against cancer”, the Brittany region, and the Brest University Hospital INNOVEO donation fund.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Bagacean C, Zdrenghea M, Tempescul A, Cristea V, Renaudineau Y (2016) Anti-CD20 monoclonal antibodies in chronic lymphocytic leukemia: from uncertainties to promises. Immunotherapy 8:569–581CrossRefPubMedGoogle Scholar
  2. 2.
    Seret G, Hanrotel C, Bendaoud B, Le Meur Y, Renaudineau Y (2013) Homozygous FCGR3A-158F mutation is associated with delayed B-cell depletion following rituximab but with preserved efficacy in a patient with refractory lupus nephritis. Clin Kidney J 6:74–76CrossRefPubMedGoogle Scholar
  3. 3.
    Devauchelle-Pensec V, Pennec Y, Morvan J, Pers JO, Daridon C, Jousse-Joulin S, Roudaut A, Jamin C, Renaudineau Y, Roué IQ, Cochener B, Youinou P, Saraux A (2007) Improvement of Sjogren’s syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum 57:310–317CrossRefPubMedGoogle Scholar
  4. 4.
    Gazeau P, Alegria GC, Devauchelle-Pensec V, Jamin C, Lemerle J, Bendaoud B, Brooks WH, Saraux A, Cornec D, Renaudineau Y (2017) Memory B cells and response to abatacept in rheumatoid arthritis. Clin Rev Allergy Immunol 53:166–176CrossRefPubMedGoogle Scholar
  5. 5.
    Gazeau P, Devauchelle-Pensec V, Pochard P, Pers JO, Saraux A, Renaudineau Y, Cornec D (2016) Abatacept efficacy in rheumatoid arthritis is dependent upon baseline blood B-cell levels. Rheumatology (Oxford) 55:1138–1140CrossRefGoogle Scholar
  6. 6.
    Bagacean C, Tempescul A, Ternant D, Banet A, Douet-Guilbert N, Bordron A, Bendaoud B, Saad H, Zdrenghea M, Berthou C, Paintaud G, Renaudineau Y (2019) 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia. J Immunother Cancer 7:22CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bagacean C, Tomuleasa C, Tempescul A et al (2019) Apoptotic resistance in chronic lymphocytic leukemia and therapeutic perspectives. Critical reviews in clinical laboratory sciences. In Press, pp 1–32Google Scholar
  8. 8.
    Nonaka M, Kimura A (2006) Genomic view of the evolution of the complement system. Immunogenetics 58:701–713CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bordet J (1895) Les leucocytes et les propriétés actives du sérum chez les vaccines. Annales de l’Institut Pasteur 9:462–506Google Scholar
  10. 10.
    Kemper C, Pangburn MK, Fishelson Z (2014) Complement nomenclature 2014. Mol Immunol 61:56–58CrossRefPubMedGoogle Scholar
  11. 11.
    Ali YM, Lynch NJ, Haleem KS, Fujita T, Endo Y, Hansen S, Holmskov U, Takahashi K, Stahl GL, Dudler T, Girija UV, Wallis R, Kadioglu A, Stover CM, Andrew PW, Schwaeble WJ (2012) The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection. PLoS Pathog 8:e1002793CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Diebolder CA, Beurskens FJ, de Jong RN, Koning RI, Strumane K, Lindorfer MA, Voorhorst M, Ugurlar D, Rosati S, Heck AJR, van de Winkel JGJ, Wilson IA, Koster AJ, Taylor RP, Ollmann Saphire E, Burton DR, Schuurman J, Gros P, Parren PWHI (2014) Complement is activated by IgG hexamers assembled at the cell surface. Science 343:1260–1263CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Raju TS (2008) Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr Opin Immunol 20:471–478CrossRefPubMedGoogle Scholar
  14. 14.
    Burton DR, Gregory L, Jefferis R (1986) Aspects of the molecular structure of IgG subclasses. Monogr Allergy 19:7–35PubMedGoogle Scholar
  15. 15.
    Cattaneo A, Neuberger MS (1987) Polymeric immunoglobulin M is secreted by transfectants of non-lymphoid cells in the absence of immunoglobulin J chain. EMBO J 6:2753–2758CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Reid KB, Porter RR (1976) Subunit composition and structure of subcomponent C1q of the first component of human complement. The Biochemical journal 155:19–23CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Czajkowsky DM, Shao Z (2009) The human IgM pentamer is a mushroom-shaped molecule with a flexural bias. Proc Natl Acad Sci U S A 106:14960–14965CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Feinstein A, Richardson N, Taussig MI (1986) Immunoglobulin flexibility in complement activation. Immunol Today 7:169–174CrossRefPubMedGoogle Scholar
  19. 19.
    Zhou W (2012) The new face of anaphylatoxins in immune regulation. Immunobiology 217:225–234CrossRefPubMedGoogle Scholar
  20. 20.
    Derer S, Beurskens FJ, Rosner T, Peipp M, Valerius T (2014) Complement in antibody-based tumor therapy. Crit Rev Immunol 34:199–214CrossRefPubMedGoogle Scholar
  21. 21.
    Chen NJ, Mirtsos C, Suh D, Lu YC, Lin WJ, McKerlie C, Lee T, Baribault H, Tian H, Yeh WC (2007) C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature 446:203–207CrossRefPubMedGoogle Scholar
  22. 22.
    Walport MJ (2001) Complement. First of two parts. N Engl J Med 344:1058–1066CrossRefPubMedGoogle Scholar
  23. 23.
    Shushakova N, Skokowa J, Schulman J, Baumann U, Zwirner J, Schmidt RE, Gessner JE (2002) C5a anaphylatoxin is a major regulator of activating versus inhibitory FcgammaRs in immune complex-induced lung disease. J Clin Invest 110:1823–1830CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Schmidt RE, Gessner JE (2005) Fc receptors and their interaction with complement in autoimmunity. Immunol Lett 100:56–67CrossRefGoogle Scholar
  25. 25.
    Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA (2006) Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 12:682–687CrossRefPubMedGoogle Scholar
  26. 26.
    Kumar V, Ali SR, Konrad S, Zwirner J, Verbeek JS, Schmidt RE, Gessner JE (2006) Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice. J Clin Invest 116:512–520CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Vetvicka V, Thornton BP, Wieman TJ, Ross GD (1997) Targeting of natural killer cells to mammary carcinoma via naturally occurring tumor cell-bound iC3b and beta-glucan-primed CR3 (CD11b/CD18). J Immunol 159:599–605PubMedGoogle Scholar
  28. 28.
    Klein E, Di Renzo L, Yefenof E (1990) Contribution of CR3, CD11b/CD18 to cytolysis by human NK cells. Mol Immunol 27:1343–1347CrossRefPubMedGoogle Scholar
  29. 29.
    Li B, Allendorf DJ, Hansen R, Marroquin J, Ding C, Cramer DE, Yan J (2006) Yeast beta-glucan amplifies phagocyte killing of iC3b-opsonized tumor cells via complement receptor 3-Syk-phosphatidylinositol 3-kinase pathway. J Immunol 177:1661–1669CrossRefPubMedGoogle Scholar
  30. 30.
    Brekke OL, Christiansen D, Fure H, Fung M, Mollnes TE (2007) The role of complement C3 opsonization, C5a receptor, and CD14 in E. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood. J Leukoc Biol 81:1404–1413CrossRefPubMedGoogle Scholar
  31. 31.
    Kennedy AD, Solga MD, Schuman TA, Chi AW, Lindorfer MA, Sutherland WM, Foley PL, Taylor RP (2003) An anti-C3b(i) mAb enhances complement activation, C3b(i) deposition, and killing of CD20+ cells by rituximab. Blood 101:1071–1079CrossRefPubMedGoogle Scholar
  32. 32.
    Kennedy AD, Beum PV, Solga MD, DiLillo DJ, Lindorfer MA, Hess CE, Densmore JJ, Williams ME, Taylor RP (2004) Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol 172:3280–3288CrossRefPubMedGoogle Scholar
  33. 33.
    Gorter A, Meri S (1999) Immune evasion of tumor cells using membrane-bound complement regulatory proteins. Immunol Today 20:576–582CrossRefPubMedGoogle Scholar
  34. 34.
    Weng WK, Levy R (2001) Expression of complement inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma. Blood 98:1352–1357CrossRefPubMedGoogle Scholar
  35. 35.
    Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna M (2001) CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood 98:3383–3389CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Meri S, Pangburn MK (1990) Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H. Proc Natl Acad Sci U S A 87:3982–3986CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Davis AE 3rd (2004) Biological effects of C1 inhibitor. Drug News Perspect 17:439–446CrossRefPubMedGoogle Scholar
  38. 38.
    Rawal N, Pangburn MK (2007) Role of the C3b-binding site on C4b-binding protein in regulating classical pathway C5 convertase. Mol Immunol 44:1105–1114CrossRefPubMedGoogle Scholar
  39. 39.
    Sanchez-Gallego JI, Groeneveld TW, Krentz S et al (2012) Analysis of binding sites on complement factor I using artificial N-linked glycosylation. J Biol Chem 287:13572–13583CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Weiler JM, Daha MR, Austen KF, Fearon DT (1976) Control of the amplification convertase of complement by the plasma protein beta1H. Proc Natl Acad Sci U S A 73:3268–3272CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse HM, Schirmer S, Gropp K, Enghardt T, Wallich R, Halbich S, Mihlan M, Schlotzer-Schrehardt U, Zipfel PF, Skerka C (2009) Factor H-related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood 114:2439–2447CrossRefPubMedGoogle Scholar
  42. 42.
    Skerka C, Chen Q, Fremeaux-Bacchi V, Roumenina LT (2013) Complement factor H related proteins (CFHRs). Mol Immunol 56:170–180CrossRefPubMedGoogle Scholar
  43. 43.
    Liu J, Miwa T, Hilliard B, Chen Y, Lambris JD, Wells AD, Song WC (2005) The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J Exp Med 201:567–577CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Varela JC, Imai M, Atkinson C, Ohta R, Rapisardo M, Tomlinson S (2008) Modulation of protective T cell immunity by complement inhibitor expression on tumor cells. Cancer Res 68:6734–6742CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Keppler OT, Moldenhauer G, Oppenlander M et al (1992) Human Golgi beta-galactoside alpha-2,6-sialyltransferase generates a group of sialylated B lymphocyte differentiation antigens. Eur J Immunol 22:2777–2781CrossRefPubMedGoogle Scholar
  46. 46.
    Bordron A, Bagacean C, Mohr A, Tempescul A, Bendaoud B, Deshayes S, Dalbies F, Buors C, Saad H, Berthou C, Pers JO, Renaudineau Y (2018) Resistance to complement activation, cell membrane hypersialylation and relapses in chronic lymphocytic leukemia patients treated with rituximab and chemotherapy. Oncotarget 9:31590–31605CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Donin N, Jurianz K, Ziporen L et al (2003) Complement resistance of human carcinoma cells depends on membrane regulatory proteins, protein kinases and sialic acid. Clin Exp Immunol 131:254–263CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Di Gaetano N, Cittera E, Nota R et al (2003) Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol 171:1581–1587CrossRefPubMedGoogle Scholar
  49. 49.
    Sato F, Ito A, Ishida T, Mori F, Takino H, Inagaki A, Ri M, Kusumoto S, Komatsu H, Iida S, Okada N, Inagaki H, Ueda R (2010) A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rgamma(null) mouse lymphoma model. Cancer Immunol Immunother 59:1791–1800CrossRefPubMedGoogle Scholar
  50. 50.
    Robak T, Lech-Maranda E, Robak P (2010) Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia. Expert Rev Anticancer Ther 10:1529–1543CrossRefPubMedGoogle Scholar
  51. 51.
    Henry J, Gottenberg JE, Rouanet S, Pavy S, Sellam J, Tubach F, Belkhir R, Mariette X, Seror R, for the Auto-Immunity and Rituximab investigators (2018) Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and risk of serious infection. Rheumatology (Oxford) 57:538–547CrossRefGoogle Scholar
  52. 52.
    Iskandar A, Hwang A, Dasanu CA (2018) Severe warm-antibody autoimmune hemolytic anemia due to multicentric Castleman disease: responding to rituximab. J Oncol Pharm Pract. In Press:1078155218816775Google Scholar
  53. 53.
    Huhn D, von Schilling C, Wilhelm M, Ho AD, Hallek M, Kuse R, Knauf W, Riedel U, Hinke A, Srock S, Serke S, Peschel C, Emmerich B, German Chronic Lymphocytic Leukemia Study Group (2001) Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood 98:1326–1331CrossRefPubMedGoogle Scholar
  54. 54.
    Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 6:443–446CrossRefPubMedGoogle Scholar
  55. 55.
    Veeramani S, Wang SY, Dahle C, Blackwell S, Jacobus L, Knutson T, Button A, Link BK, Weiner GJ (2011) Rituximab infusion induces NK activation in lymphoma patients with the high-affinity CD16 polymorphism. Blood 118:3347–3349CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Zent CS, Elliott MR (2017) Maxed out macs: physiologic cell clearance as a function of macrophage phagocytic capacity. FEBS J 284:1021–1039CrossRefPubMedGoogle Scholar
  57. 57.
    Grandjean CL, Montalvao F, Celli S, Michonneau D, Breart B, Garcia Z, Perro M, Freytag O, Gerdes CA, Bousso P (2016) Intravital imaging reveals improved Kupffer cell-mediated phagocytosis as a mode of action of glycoengineered anti-CD20 antibodies. Sci Rep 6:34382CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gul N, Babes L, Siegmund K et al (2014) Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. J Clin Invest 124:812–823CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Montalvao F, Garcia Z, Celli S, Breart B, Deguine J, van Rooijen N, Bousso P (2013) The mechanism of anti-CD20-mediated B cell depletion revealed by intravital imaging. J Clin Invest 123:5098–5103CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Semac I, Palomba C, Kulangara K, Klages N, van Echten-Deckert G, Borisch B, Hoessli DC (2003) Anti-CD20 therapeutic antibody rituximab modifies the functional organization of rafts/microdomains of B lymphoma cells. Cancer Res 63:534–540PubMedGoogle Scholar
  61. 61.
    Beum PV, Lindorfer MA, Beurskens F, Stukenberg PT, Lokhorst HM, Pawluczkowycz AW, Parren PWHI, van de Winkel JGJ, Taylor RP (2008) Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol 181:822–832CrossRefPubMedGoogle Scholar
  62. 62.
    Hagenbeek A, Gadeberg O, Johnson P, Moller Pedersen L, Walewski J, Hellmann A, Link BK, Robak T, Wojtukiewicz M, Pfreundschuh M, Kneba M, Engert A, Sonneveld P, Flensburg M, Petersen J, Losic N, Radford J (2008) First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 111:5486–5495CrossRefPubMedGoogle Scholar
  63. 63.
    Tempescul A, Bagacean C, Riou C, Bendaoud B, Hillion S, Debant M, Buors C, Berthou C, Renaudineau Y (2016) Ofatumumab capacity to deplete B cells from chronic lymphocytic leukaemia is affected by C4 complement exhaustion. Eur J Haematol 96:229–235CrossRefPubMedGoogle Scholar
  64. 64.
    Nguyen DT, Amess JA, Doughty H, Hendry L, Diamond LW (1999) IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin’s lymphoma and lymphoproliferative disorders: evaluation of response on 48 patients. Eur J Haematol 62:76–82CrossRefPubMedGoogle Scholar
  65. 65.
    Winkler U, Jensen M, Manzke O et al (1999) Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 94:2217–2224PubMedGoogle Scholar
  66. 66.
    Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A, Hx-CD20-406 Study Investigators (2010) Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 28:1749–1755CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Martinez C, Diaz-Lopez A, Rodriguez-Calvillo M et al (2016) Phase II trial of ofatumumab plus ESHAP (O-ESHAP) as salvage treatment for patients with relapsed or refractory classical Hodgkin lymphoma after first-line chemotherapy. Br J Haematol 174:859–867CrossRefPubMedGoogle Scholar
  68. 68.
    Bello C, Veliz M, Pinilla-Ibarz J (2011) Ofatumumab in the treatment of low-grade non-Hodgkin’s lymphomas and chronic lymphocytic leukemia. Expert Rev Clin Immunol 7:295–300CrossRefPubMedGoogle Scholar
  69. 69.
    Czuczman MS, Fayad L, Delwail V, Cartron G, Jacobsen E, Kuliczkowski K, Link BK, Pinter-Brown L, Radford J, Hellmann A, Gallop-Evans E, DiRienzo CG, Goldstein N, Gupta I, Jewell RC, Lin TS, Lisby S, Schultz M, Russell CA, Hagenbeek A, on behalf of the 405 Study Investigators (2012) Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 119:3698–3704CrossRefPubMedGoogle Scholar
  70. 70.
    Milani C, Castillo J (2009) Veltuzumab, an anti-CD20 mAb for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and immune thrombocytopenic purpura. Curr Opin Mol Ther 11:200–207PubMedGoogle Scholar
  71. 71.
    Morschhauser F, Leonard JP, Fayad L, Coiffier B, Petillon MO, Coleman M, Schuster SJ, Dyer MJS, Horne H, Teoh N, Wegener WA, Goldenberg DM (2009) Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol 27:3346–3353CrossRefPubMedGoogle Scholar
  72. 72.
    Morschhauser F, Marlton P, Vitolo U, Linden O, Seymour JF, Crump M, Coiffier B, Foa R, Wassner E, Burger HU, Brennan B, Mendila M (2010) Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol 21:1870–1876CrossRefPubMedGoogle Scholar
  73. 73.
    Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G (2012) Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood 119:5126–5132CrossRefPubMedGoogle Scholar
  74. 74.
    Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, Sondermann P, Jager C, Strein P, Fertig G, Friess T, Schull C, Bauer S, Dal Porto J, del Nagro C, Dabbagh K, Dyer MJS, Poppema S, Klein C, Umana P (2010) Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115:4393–4402CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M (2014) Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370:1101–1110CrossRefPubMedGoogle Scholar
  76. 76.
    Wayne JL, Ganjoo KN, Pohlman BL et al, editors. Efficacy of ocaratuzumab (AME-133v) in relapsed follicular lymphoma patients refractory to prior rituximab. ASCO Meeting; 2012Google Scholar
  77. 77.
    Tobinai K, Ogura M, Kobayashi Y, Uchida T, Watanabe T, Oyama T, Maruyama D, Suzuki T, Mori M, Kasai M, Cronier D, Wooldridge JE, Koshiji M (2011) Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma. Cancer Sci 102:432–438CrossRefPubMedGoogle Scholar
  78. 78.
    Church AK, VanDerMeid KR, Baig NA et al (2016) Anti-CD20 monoclonal antibody-dependent phagocytosis of chronic lymphocytic leukaemia cells by autologous macrophages. Clin Exp Immunol 183:90–101CrossRefPubMedGoogle Scholar
  79. 79.
    Sawas A, Farber CM, Schreeder MT, Khalil MY, Mahadevan D, Deng C, Amengual JE, Nikolinakos PG, Kolesar JM, Kuhn JG, Sportelli P, Miskin HP, O’Connor OA (2017) A phase 1/2 trial of ublituximab, a novel anti-CD20 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab. Br J Haematol 177:243–253CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Ward E, Mittereder N, Kuta E, Sims GP, Bowen MA, Dall’Acqua W, Tedder T, Kiener P, Coyle AJ, Wu H, Jallal B, Herbst R (2011) A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo. Br J Haematol 155:426–437CrossRefPubMedGoogle Scholar
  81. 81.
    Jurczak W, Bryk AH, Mensah P, Gałązka K, Trofimiuk–Müldner M, Wyrobek Ł, Sawiec A, Skotnicki AB (2016) Single-agent MOR208 salvage and maintenance therapy in a patient with refractory/relapsing diffuse large B-cell lymphoma: a case report. J Med Case Rep 10:123CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Horton HM, Bernett MJ, Pong E, Peipp M, Karki S, Chu SY, Richards JO, Vostiar I, Joyce PF, Repp R, Desjarlais JR, Zhukovsky EA (2008) Potent in vitro and in vivo activity of an Fc-engineered anti-CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res 68:8049–8057CrossRefPubMedGoogle Scholar
  83. 83.
    Woyach JA, Awan F, Flinn IW, Berdeja JG, Wiley E, Mansoor S, Huang Y, Lozanski G, Foster PA, Byrd JC (2014) A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. Blood 124:3553–3560CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Cardarelli PM, Rao-Naik C, Chen S, Huang H, Pham A, Moldovan-Loomis MC, Pan C, Preston B, Passmore D, Liu J, Kuhne MR, Witte A, Blanset D, King DJ (2010) A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies. Cancer Immunol Immunother 59:257–265CrossRefPubMedGoogle Scholar
  85. 85.
    Wei G, Wang J, Huang H, Zhao Y (2017) Novel immunotherapies for adult patients with B-lineage acute lymphoblastic leukemia. J Hematol Oncol 10:150CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Leonard JP, Coleman M, Ketas JC, Chadburn A, Ely S, Furman RR, Wegener WA, Hansen HJ, Ziccardi H, Eschenberg M, Gayko U, Cesano A, Goldenberg DM (2003) Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol 21:3051–3059CrossRefPubMedGoogle Scholar
  87. 87.
    Thieblemont C, Bouafia F, Hornez E et al (2004) Maintenance therapy with a monthly injection of alemtuzumab prolongs response duration in patients with refractory B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL). Leuk Lymphoma 45:711–714CrossRefPubMedGoogle Scholar
  88. 88.
    Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA, Shen Z, Patel N, Tai YT, Chauhan D, Mitsiades C, Prabhala R, Raje N, Anderson KC, Stover DR, Munshi NC (2009) Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood 114:371–379CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Czuczman MS, Leonard JP, Jung S, Johnson JL, Hsi ED, Byrd JC, Cheson BD (2012) Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann Oncol 23:2356–2362CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Czuczman MS, Leonard JP, Jung S, Johnson JL, Hsi ED, Byrd JC, Cheson BD (2018) Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann Oncol 29:2271CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Bensinger W, Maziarz RT, Jagannath S, Spencer A, Durrant S, Becker PS, Ewald B, Bilic S, Rediske J, Baeck J, Stadtmauer EA (2012) A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma. Br J Haematol 159:58–66CrossRefPubMedGoogle Scholar
  92. 92.
    Byrd JC, Kipps TJ, Flinn IW, Cooper M, Odenike O, Bendiske J, Rediske J, Bilic S, Dey J, Baeck J, O’Brien S (2012) Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk Lymphoma 53:2136–2142CrossRefPubMedGoogle Scholar
  93. 93.
    Fanale M, Assouline S, Kuruvilla J, Solal-Céligny P, Heo DS, Verhoef G, Corradini P, Abramson JS, Offner F, Engert A, Dyer MJS, Carreon D, Ewald B, Baeck J, Younes A, Freedman AS (2014) Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol 164:258–265CrossRefPubMedGoogle Scholar
  94. 94.
    de Vos S, Forero-Torres A, Ansell SM, Kahl B, Cheson BD, Bartlett NL, Furman RR, Winter JN, Kaplan H, Timmerman J, Whiting NC, Drachman JG, Advani R (2014) A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors. J Hematol Oncol 7:44CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Furman RR, Forero-Torres A, Shustov A, Drachman JG (2010) A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia. Leuk Lymphoma 51:228–235CrossRefPubMedGoogle Scholar
  96. 96.
    Hussein M, Berenson JR, Niesvizky R, Munshi N, Matous J, Sobecks R, Harrop K, Drachman JG, Whiting N (2010) A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 95:845–848CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Dorner T, Posch MG, Li Y et al (2019) Treatment of primary Sjogren’s syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity. Ann Rheum Dis In Press 78:641–647CrossRefPubMedGoogle Scholar
  98. 98.
    Silence K, Dreier T, Moshir M, Ulrichts P, Gabriels SME, Saunders M, Wajant H, Brouckaert P, Huyghe L, van Hauwermeiren T, Thibault A, de Haard HJ (2014) ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade. mAbs 6:523–532CrossRefPubMedGoogle Scholar
  99. 99.
    Krause G, Baki I, Kerwien S, Knödgen E, Neumann L, Göckeritz E, Landwehr T, Heider KH, Hallek M (2016) Cytotoxicity of the CD37 antibody BI 836826 against chronic lymphocytic leukaemia cells in combination with chemotherapeutic agents or PI3K inhibitors. Br J Haematol 173:791–794CrossRefPubMedGoogle Scholar
  100. 100.
    Robak T, Hellmann A, Kloczko J, Loscertales J, Lech-Maranda E, Pagel JM, Mato A, Byrd JC, Awan FT, Hebart H, Garcia-Marco JA, Hill BT, Hallek M, Eisenfeld AJ, Stromatt SC, Jaeger U (2017) Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. Br J Haematol 176:618–628CrossRefPubMedGoogle Scholar
  101. 101.
    Pagel JM, Spurgeon SE, Byrd JC, Awan FT, Flinn IW, Lanasa MC, Eisenfeld AJ, Stromatt SC, Gopal AK (2015) Otlertuzumab (TRU-016), an anti-CD37 monospecific ADAPTIR() therapeutic protein, for relapsed or refractory NHL patients. Br J Haematol 168:38–45CrossRefPubMedGoogle Scholar
  102. 102.
    Rasche L, Duell J, Castro IC, Dubljevic V, Chatterjee M, Knop S, Hensel F, Rosenwald A, Einsele H, Topp MS, Brandlein S (2015) GRP78-directed immunotherapy in relapsed or refractory multiple myeloma - results from a phase 1 trial with the monoclonal immunoglobulin M antibody PAT-SM6. Haematologica 100:377–384CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Bajaj J, Konuma T, Lytle NK, Kwon HY, Ablack JN, Cantor JM, Rizzieri D, Chuah C, Oehler VG, Broome EH, Ball ED, van der Horst EH, Ginsberg MH, Reya T (2016) CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell 30:792–805CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Baz RC, Zonder JA, Gasparetto C, Reu FJ, Strout V (2016) Phase I study of anti-GM2 ganglioside monoclonal antibody BIW-8962 as monotherapy in patients with previously treated multiple myeloma. Oncol Ther 4:287–301CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Hansson M, Gimsing P, Badros A, Niskanen TM, Nahi H, Offner F, Salomo M, Sonesson E, Mau-Sorensen M, Stenberg Y, Sundberg A, Teige I, van Droogenbroeck J, Wichert S, Zangari M, Frendeus B, Korsgren M, Poelman M, Tricot G (2015) A phase I dose-escalation study of antibody BI-505 in relapsed/refractory multiple myeloma. Clin Cancer Res 21:2730–2736CrossRefPubMedGoogle Scholar
  106. 106.
    Wichert S, Juliusson G, Johansson A, Sonesson E, Teige I, Wickenberg AT, Frendeus B, Korsgren M, Hansson M (2017) A single-arm, open-label, phase 2 clinical trial evaluating disease response following treatment with BI-505, a human anti-intercellular adhesion molecule-1 monoclonal antibody, in patients with smoldering multiple myeloma. PLoS One 12:e0171205CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Cuesta-Mateos C, Alcaraz-Serna A, Somovilla-Crespo B, Munoz-Calleja C (2017) Monoclonal antibody therapies for hematological malignancies: not just lineage-specific targets. Front Immunol 8:1936Google Scholar
  108. 108.
    Krupka C, Lichtenegger FS, Kohnke T et al (2017) Targeting CD157 in AML using a novel, Fc-engineered antibody construct. Oncotarget 8:35707–35717CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Chehab S, Panjic EH, Gleason C, Lonial S, Nooka AK (2018) Daratumumab and its use in the treatment of relapsed and/or refractory multiple myeloma. Future Oncol 14:3111–3121CrossRefPubMedGoogle Scholar
  110. 110.
    Shah NN, Singavi AK, Harrington A (2018) Daratumumab in primary effusion lymphoma. N Engl J Med 379:689–690CrossRefPubMedGoogle Scholar
  111. 111.
    Ganzel C, Kharit M, Duksin C, Rowe JM (2018) Daratumumab for relapsed/refractory Philadelphia-positive acute lymphoblastic leukemia. Haematologica 103:e489–e490CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Buteyn NJ, Fatehchand K, Santhanam R, Fang H, Dettorre GM, Gautam S, Harrington BK, Henderson SE, Merchand-Reyes G, Mo X, Benson DM, Carson WE III, Vasu S, Byrd JC, Butchar JP, Tridandapani S (2018) Anti-leukemic effects of all-trans retinoic acid in combination with daratumumab in acute myeloid leukemia. Int Immunol 30:375–383CrossRefPubMedGoogle Scholar
  113. 113.
    Richardson PG, Attal M, Campana F, le-Guennec S, Hui AM, Risse ML, Corzo K, Anderson KC (2018) Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA phase III study design. Future Oncol 14:1035–1047CrossRefPubMedGoogle Scholar
  114. 114.
    van de Donk NW, Janmaat ML, Mutis T et al (2016) Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. Immunol Rev 270:95–112CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Busch L, Mougiakakos D, Buttner-Herold M et al (2018) Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway. Leukemia 32:2445–2458CrossRefPubMedGoogle Scholar
  116. 116.
    Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, Signorovitch JE, Makenbaeva D, Mekan S, Sy O, Weisel K, Richardson PG (2018) Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer 124:4032–4043CrossRefPubMedGoogle Scholar
  117. 117.
    Inoue Y, Endo S, Matsuno N, Kikukawa Y, Shichijo T, Koga K, Takaki A, Iwanaga K, Nishimura N, Fuji S, Fukuda T, Nosaka K, Matsuoka M (2019) Safety of mogamulizumab for relapsed ATL after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 54:338–342CrossRefPubMedGoogle Scholar
  118. 118.
    (2018) Mogamulizumab tops standard of care for CTCL. Cancer Discov 8:OF1Google Scholar
  119. 119.
    Fujita Y, Nakaya A, Fujita S et al (2016) Mogamulizumab treatment of refractory peripheral T-cell lymphoma following autologous stem cell transplantation: a case report. Mol Clin Oncol 4:151–153CrossRefPubMedGoogle Scholar
  120. 120.
    Tobinai K (2016) Disease-oriented treatment of T/NK-cell lymphomas. [Rinsho ketsueki. Jpn J Clin Hematol 57:1044–1051Google Scholar
  121. 121.
    Kashyap MK, Amaya-Chanaga CI, Kumar D, Simmons B, Huser N, Gu Y, Hallin M, Lindquist K, Yafawi R, Choi MY, Amine AA, Rassenti LZ, Zhang C, Liu SH, Smeal T, Fantin VR, Kipps TJ, Pernasetti F, Castro JE (2017) Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia. J Hematol Oncol 10:112CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Zhang Y, Saavedra E, Tang R, Gu Y, Lappin P, Trajkovic D, Liu SH, Smeal T, Fantin V, de Botton S, Legrand O, Delhommeau F, Pernasetti F, Louache F (2017) Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143). Sci Rep 7:7305CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    He SZ, Busfield S, Ritchie DS, Hertzberg MS, Durrant S, Lewis ID, Marlton P, McLachlan AJ, Kerridge I, Bradstock KF, Kennedy G, Boyd AW, Yeadon TM, Lopez AF, Ramshaw HS, Iland H, Bamford S, Barnden M, DeWitte M, Basser R, Roberts AW (2015) A phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia. Leuk Lymphoma 56:1406–1415CrossRefPubMedGoogle Scholar
  124. 124.
    Reichert JM (2017) Antibodies to watch in 2017. mAbs 9:167–181CrossRefPubMedGoogle Scholar
  125. 125.
    Assi R, Kantarjian H, Ravandi F, Daver N (2018) Immune therapies in acute myeloid leukemia: a focus on monoclonal antibodies and immune checkpoint inhibitors. Curr Opin Hematol 25:136–145PubMedGoogle Scholar
  126. 126.
    Punt CJ, Nagy A, Douillard JY et al (2002) Edrecolomab alone or in combination with fluorouracil and folinic acid in the adjuvant treatment of stage III colon cancer: a randomised study. Lancet 360:671–677CrossRefPubMedGoogle Scholar
  127. 127.
    Murthy RK, Raghavendra AS, Hess KR, Fujii T, Lim B, Barcenas CH, Zhang H, Chavez-Mac-Gregor M, Mittendorf EA, Litton JK, Giordano SH, Thompson AM, Valero V, Moulder SL, Tripathy D, Ueno NT (2018) Neoadjuvant pertuzumab-containing regimens improve pathologic complete response rates in stage II to III HER-2/neu-positive breast cancer: a retrospective, single institution experience. Clin Breast Cancer 18:e1283–e1288CrossRefPubMedGoogle Scholar
  128. 128.
    Roviello G, Generali D (2018) Pertuzumab therapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer. Lancet Oncol 19:1270–1272CrossRefPubMedGoogle Scholar
  129. 129.
    Martin AP, Downing J, Cochrane M, Collins B, Francis B, Haycox A, Alfirevic A, Pirmohamed M (2018) Trastuzumab uptake in HER2-positive breast cancer patients: a systematic review and meta-analysis of observational studies. Crit Rev Oncol Hematol 130:92–107CrossRefPubMedGoogle Scholar
  130. 130.
    Chen ZL, Zhao A, Li P et al (2018) Clinical use of trastuzumab combined with different chemotherapy regimens in multi-line treatment of advanced human epidermal growth factor receptor 2-positive gastric cancer: a case report. Oncol Lett 16:4614–4620PubMedPubMedCentralGoogle Scholar
  131. 131.
    Fala L (2016) Portrazza (necitumumab), an IgG1 monoclonal antibody, FDA approved for advanced squamous non-small-cell lung cancer. Am Health Drug Benefits 9:119–122PubMedPubMedCentralGoogle Scholar
  132. 132.
    Addeo R, Montella L, Mastella A, Vincenzi B, Mazzone S, Ricciardiello F, del Prete S (2018) Maintenance therapy with biweekly cetuximab: optimizing schedule can preserve activity and improves compliance in advanced head and neck cancer. Oncology 95:353–359CrossRefPubMedGoogle Scholar
  133. 133.
    Knodler M, Korfer J, Kunzmann V et al (2018) Randomised phase II trial to investigate catumaxomab (anti-EpCAM x anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer. Br J Cancer 119:296–302CrossRefPubMedGoogle Scholar
  134. 134.
    Trzpis M, McLaughlin PM, de Leij LM, Harmsen MC (2007) Epithelial cell adhesion molecule: more than a carcinoma marker and adhesion molecule. Am J Pathol 171:386–395CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Iqbal N, Iqbal N (2014) Human epidermal growth factor receptor 2 (HER2) in cancers: overexpression and therapeutic implications. Mol Biol Int 2014:852748CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Normanno N, De Luca A, Bianco C et al (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2–16CrossRefPubMedGoogle Scholar
  137. 137.
    Navid F, Santana VM, Barfield RC (2010) Anti-GD2 antibody therapy for GD2-expressing tumors. Curr Cancer Drug Targets 10:200–209CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship THJ, Atkinson JP (2007) Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol 44:111–122CrossRefPubMedGoogle Scholar
  139. 139.
    Stuhlinger W, Kourilsky O, Kanfer A, Sraer JD (1974) Letter: Haemolytic-uraemic syndrome: evidence for intravascular C3 activation. Lancet 2:788–789CrossRefPubMedGoogle Scholar
  140. 140.
    Hillmen P, Muus P, Roth A et al (2013) Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 162:62–73CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Keating GM (2013) Eculizumab: a review of its use in atypical haemolytic uraemic syndrome. Drugs 73:2053–2066CrossRefPubMedGoogle Scholar
  142. 142.
    Wong EK, Goodship TH, Kavanagh D (2013) Complement therapy in atypical haemolytic uraemic syndrome (aHUS). Mol Immunol 56:199–212CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Lee JW, Peffault de Latour R, Brodsky RA, Jang JH, Hill A, Röth A, Schrezenmeier H, Wilson A, Marantz JL, Maciejewski JP (2019) Effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia in the International PNH Registry. Am J Hematol 94:E37–E41CrossRefPubMedGoogle Scholar
  144. 144.
    Kinoshita T (2018) Congenital defects in the expression of the glycosylphosphatidylinositol-anchored complement regulatory proteins CD59 and decay-accelerating factor. Semin Hematol 55:136–140CrossRefPubMedGoogle Scholar
  145. 145.
    Dalakas MC (2019) Immunotherapy in myasthenia gravis in the era of biologics. Nat Rev Neurol 15:113–124CrossRefPubMedGoogle Scholar
  146. 146.
    Kello N, Khoury LE, Marder G et al (2018) Secondary thrombotic microangiopathy in systemic lupus erythematosus and antiphospholipid syndrome, the role of complement and use of eculizumab: case series and review of literature. Seminars in arthritis and rheumatism. In PressGoogle Scholar
  147. 147.
    McNamara LA, Topaz N, Wang X et al (2017) High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. MMWR Morb Mortal Wkly Rep 66:734–737CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Ross SC, Densen P (1984) Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine 63:243–273CrossRefPubMedGoogle Scholar
  149. 149.
    Truedsson L, Bengtsson AA, Sturfelt G (2007) Complement deficiencies and systemic lupus erythematosus. Autoimmunity 40:560–566CrossRefPubMedGoogle Scholar
  150. 150.
    Herreman G, Ferme I, Diebold J, Baviera E, Audouin J, Bazin C, Godeau P (1983) Gougerot-Sjogren syndrome, periarteritis nodosa, non-Hodgkin’s lymphoplasmocytic lymphoma and acquired C4 deficiency. Ann Med Interne 134:19–25Google Scholar
  151. 151.
    Liesmaa I, Paakkanen R, Jarvinen A, Valtonen V, Lokki ML (2018) Clinical features of patients with homozygous complement C4A or C4B deficiency. PLoS One 13:e0199305CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Bossi F, Tripodo C, Rizzi L, Bulla R, Agostinis C, Guarnotta C, Munaut C, Baldassarre G, Papa G, Zorzet S, Ghebrehiwet B, Ling GS, Botto M, Tedesco F (2014) C1q as a unique player in angiogenesis with therapeutic implication in wound healing. Proc Natl Acad Sci U S A 111:4209–4214CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Ballanti E, Perricone C, Greco E, Ballanti M, di Muzio G, Chimenti MS, Perricone R (2013) Complement and autoimmunity. Immunol Res 56:477–491CrossRefPubMedGoogle Scholar
  154. 154.
    Chen M, Daha MR, Kallenberg CG (2010) The complement system in systemic autoimmune disease. J Autoimmun 34:J276–J286CrossRefPubMedGoogle Scholar
  155. 155.
    Wagner E, Frank MM (2010) Therapeutic potential of complement modulation. Nat Rev Drug Discov 9:43–56CrossRefPubMedGoogle Scholar
  156. 156.
    Barilla-Labarca ML, Toder K, Furie R (2013) Targeting the complement system in systemic lupus erythematosus and other diseases. Clin Immunol 148:313–321CrossRefPubMedGoogle Scholar
  157. 157.
    Durigutto P, Macor P, Ziller F, de Maso L, Fischetti F, Marzari R, Sblattero D, Tedesco F (2013) Prevention of arthritis by locally synthesized recombinant antibody neutralizing complement component C5. PLoS One 8:e58696CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Macor P, Durigutto P, De Maso L et al (2012) Treatment of experimental arthritis by targeting synovial endothelium with a neutralizing recombinant antibody to C5. Arthritis Rheum 64:2559–2567CrossRefPubMedGoogle Scholar
  159. 159.
    Rodriguez-Pinto I, Espinosa G, Cervera R (2016) Catastrophic antiphospholipid syndrome: the current management approach. Best Pract Res Clin Rheumatol 30:239–249CrossRefPubMedGoogle Scholar
  160. 160.
    Ward PA, Guo RF, Riedemann NC (2012) Manipulation of the complement system for benefit in sepsis. Crit Care Res Pract 2012:427607PubMedPubMedCentralGoogle Scholar
  161. 161.
    Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, Baumgart T, Shugarts S, Lohr L, Dang T, Miao S, Zeng Y, Fan P, Zhang P, Johnson D, Powers J, Jaen J, Charo I, Schall TJ (2016) Characterization of pharmacologic and pharmacokinetic properties of CCX168, a potent and selective orally administered complement 5a receptor inhibitor, based on preclinical evaluation and randomized phase 1 clinical study. PLoS One 11:e0164646CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, Burst V, Grundmann F, Jadoul M, Szombati I, Tesař V, Segelmark M, Potarca A, Schall TJ, Bekker P, CLEAR Study Group (2017) Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 28:2756–2767CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, Seitz LC, Penfold MET, Gan L, Hu P, Lu B, Gerard NP, Gerard C, Schall TJ, Jaen JC, Falk RJ, Jennette JC (2014) C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol 25:225–231CrossRefPubMedGoogle Scholar
  164. 164.
    Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Köhl J, Gerard C, Sarma JV, Ward PA (2008) Functional roles for C5a receptors in sepsis. Nat Med 14:551–557CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Weber BH, Charbel Issa P, Pauly D, Herrmann P, Grassmann F, Holz FG (2014) The role of the complement system in age-related macular degeneration. Dtsch Arztebl Int 111:133–138PubMedPubMedCentralGoogle Scholar
  166. 166.
    Schejbel L, Skattum L, Hagelberg S, Åhlin A, Schiller B, Berg S, Genel F, Truedsson L, Garred P (2011) Molecular basis of hereditary C1q deficiency--revisited: identification of several novel disease-causing mutations. Genes Immun 12:626–634CrossRefPubMedGoogle Scholar
  167. 167.
    Pickering MC, Botto M, Taylor PR, Lachmann PJ, Walport MJ (2000) Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv Immunol 76:227–324CrossRefPubMedGoogle Scholar
  168. 168.
    Ekinci Z, Ozturk K (2018) Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma. Lupus 27:134–138CrossRefPubMedGoogle Scholar
  169. 169.
    Damato E, Chilov M, Lee R, Singh A, Harper S, Dick A (2011) Plasma exchange and rituximab in the management of acute occlusive retinal vasculopathy secondary to systemic lupus erythematosus. Ocul Immunol Inflamm 19:379–381CrossRefPubMedGoogle Scholar
  170. 170.
    Costa R, Fazal S, Kaplan RB, Spero J, Costa R (2013) Successful plasma exchange combined with rituximab therapy in aggressive APS-related cutaneous necrosis. Clin Rheumatol 32(Suppl 1):S79–S82CrossRefPubMedGoogle Scholar
  171. 171.
    Abisror N, Mekinian A, Brechignac S, Ruffatti A, Carbillon L, Fain O (2015) Inefficacy of plasma exchanges associated to rituximab in refractory obstetrical antiphospholipid syndrome. Presse Med 44:100–102CrossRefPubMedGoogle Scholar
  172. 172.
    Middleton O, Cosimo E, Dobbin E, McCaig AM, Clarke C, Brant AM, Leach MT, Michie AM, Wheadon H (2015) Complement deficiencies limit CD20 monoclonal antibody treatment efficacy in CLL. Leukemia 29:107–114CrossRefPubMedGoogle Scholar
  173. 173.
    Fust G, Czink E, Minh D et al (1985) Depressed classical complement pathway activities in chronic lymphocytic leukaemia. Clin Exp Immunol 60:489–495PubMedPubMedCentralGoogle Scholar
  174. 174.
    Klepfish A, Gilles L, Ioannis K, Rachmilewitz EA, Schattner A (2009) Enhancing the action of rituximab in chronic lymphocytic leukemia by adding fresh frozen plasma: complement/rituximab interactions & clinical results in refractory CLL. Annals of the New York Academy of Sciences 1173:865–873Google Scholar
  175. 175.
    Charbonneau B, Maurer MJ, Fredericksen ZS, Zent CS, Link BK, Novak AJ, Ansell SM, Weiner GJ, Wang AH, Witzig TE, Dogan A, Slager SL, Habermann TM, Cerhan JR (2012) Germline variation in complement genes and event-free survival in follicular and diffuse large B-cell lymphoma. Am J Hematol 87:880–885CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Racila E, Link BK, Weng WK, Witzig TE, Ansell S, Maurer MJ, Huang J, Dahle C, Halwani A, Levy R, Weiner GJ (2008) A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma. Clin Cancer Res 14:6697–6703CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Cornec D, Tempescul A, Querellou S, Hutin P, Pers JO, Jamin C, Bendaoud B, Berthou C, Renaudineau Y, Youinou P (2012) Identification of patients with indolent B cell lymphoma sensitive to rituximab monotherapy. Ann Hematol 91:715–721CrossRefPubMedGoogle Scholar
  178. 178.
    Ytting H, Christensen IJ, Thiel S, Jensenius JC, Nielsen HJ (2005) Serum mannan-binding lectin-associated serine protease 2 levels in colorectal cancer: relation to recurrence and mortality. Clin Cancer Res 11:1441–1446CrossRefPubMedGoogle Scholar
  179. 179.
    Bouwens TA, Trouw LA, Veerhuis R et al (2015) Complement activation in glioblastoma multiforme pathophysiology: evidence from serum levels and presence of complement activation products in tumor tissue. J Neuroimmunol 278:271–276CrossRefPubMedGoogle Scholar
  180. 180.
    Zha H, Wang X, Zhu Y, Chen D, Han X, Yang F, Gao J, Hu C, Shu C, Feng Y, Tan Y, Zhang J, Li Y, Wan YY, Guo B, Zhu B (2019) Intracellular activation of complement C3 leads to PD-L1 antibody treatment resistance by modulating tumor-associated macrophages. Cancer Immunol Res 7:193–207CrossRefPubMedGoogle Scholar
  181. 181.
    Francian A, Namen S, Stanley M et al (2018) Intratumoral delivery of antigen with complement C3-bound liposomes reduces tumor growth in mice. Nanomedicine. In PressGoogle Scholar
  182. 182.
    Xu W, Miao KR, Zhu DX, Fang C, Zhu HY, Dong HJ, Wang DM, Wu YJ, Qiao C, Li JY (2011) Enhancing the action of rituximab by adding fresh frozen plasma for the treatment of fludarabine refractory chronic lymphocytic leukemia. International journal of cancer Journal international du cancer 128:2192–2201CrossRefPubMedGoogle Scholar
  183. 183.
    Tammen A, Derer S, Schwanbeck R, Rösner T, Kretschmer A, Beurskens FJ, Schuurman J, Parren PWHI, Valerius T (2017) Monoclonal antibodies against epidermal growth factor receptor acquire an ability to kill tumor cells through complement activation by mutations that selectively facilitate the hexamerization of IgG on opsonized cells. J Immunol 198:1585–1594CrossRefPubMedGoogle Scholar
  184. 184.
    Yu J, Wang W, Huang H (2019) Efficacy and safety of bispecific T-cell engager (BiTE) antibody blinatumomab for the treatment of relapsed/refractory acute lymphoblastic leukemia and non-Hodgkin’s lymphoma: a systemic review and meta-analysis. Hematology 24:199–207CrossRefPubMedGoogle Scholar
  185. 185.
    Macor P, Secco E, Mezzaroba N, Zorzet S, Durigutto P, Gaiotto T, de Maso L, Biffi S, Garrovo C, Capolla S, Tripodo C, Gattei V, Marzari R, Tedesco F, Sblattero D (2015) Bispecific antibodies targeting tumor-associated antigens and neutralizing complement regulators increase the efficacy of antibody-based immunotherapy in mice. Leukemia 29:406–414CrossRefPubMedGoogle Scholar
  186. 186.
    Hillion S, Arleevskaya MI, Brooks WH et al (2019) The innate part of the adaptive immune system. Clin Rev Allerg Immunol. In PressGoogle Scholar
  187. 187.
    Guia S, Vivier E, Narni-Mancinelli E (2019) Helper-like innate lymphoid cells: definition, functions and clinical implications in inflammatory diseases and cancer. Clin Rev Allerg Immunol. In PressGoogle Scholar
  188. 188.
    Grasseau A, Boudigou M, Le Pottier L et al (2019) Innate B-cells: the archetype of protective immune cells. Clin Rev Allerg Immunol. In PressGoogle Scholar
  189. 189.
    Brilland B, Scherlinger M, Khoryati L et al (2019) Platelets and IgE: shaping the innate immune response in systemic lupus erythematosus. Clin Rev Allerg Immunol. In PressGoogle Scholar
  190. 190.
    Maddur MS, Lacroix-Desmazes S, Dimitrov JD et al (2019) Natural antibodies: from first line defense against pathogens to perpetual immune homeostasis. Clin Rev Allerg Immunol. In PressGoogle Scholar
  191. 191.
    Defendia F, Thielensb NM, Clavarinoa G, Cesbron JY, Dumestre-Pérard C (2019) Autoantibodies targeting complement components and associated diseases. Clin Rev Allerg Immunol. In PressGoogle Scholar
  192. 192.
    Arleevskaya MI, Larionova RV, Brooks WH, Bettacchioli E, Renaudineau Y (2019) TLR, infections and rheumatoid arthritis. Clin Rev Allerg Immunol. In PressGoogle Scholar
  193. 193.
    Arleevskaya MI, Aminov R, Brooks WH, Manukyan G, Renaudineau Y (2019) Editorial: shaping oh human immune system and metabolic processes by viruses and microorganisms. Front Microbiol 10:816CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Charras A, Arvaniti P, Le Dantec C et al (2019) JAK1/2 inhibitors suppress epigenetic reprogramming of two innate immune cytokines (IFNα, IFNγ) and reactive oxygen species: a promise for patients with Sjögren’s syndrome. Clin Rev Allerg Immunol. In PressGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Inserm UMR1227, B lymphocytes and autoimmunityUniversity of BrestBrestFrance
  2. 2.Service d’HématologieCHU de BrestBrestFrance
  3. 3.Laboratory of Immunology and ImmunotherapyCHU de BrestBrestFrance

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