Advertisement

Progress and Trends in Complement Therapeutics

  • Daniel RicklinEmail author
  • John D. Lambris
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 735)

Abstract

The past few years have proven to be a highly successful and exciting period for the field of complement-directed drug discovery and development. Driven by promising experiences with the first marketed complement drugs, increased knowledge about the involvement of complement in health and disease, and improvements in structural and analytical techniques as well as animal models of disease, the field has seen a surge in creative approaches to therapeutically intervene at various stages of the cascade. An impressive panel of compounds that show promise in clinical trials is meanwhile being lined up in the pipelines of both small biotechnology and big pharmaceutical companies. Yet with this new focus on complement-targeted therapeutics, important questions concerning target selection, point and length of intervention, safety, and drug delivery emerge. In view of the diversity of the clinical disorders involving abnormal complement activity or regulation, which include both acute and chronic diseases and affect a wide range of organs, diverse yet specifically tailored therapeutic approaches may be needed to shift complement back into balance. This chapter highlights the key changes in the field that shape our current perception of complement-targeted drugs and provides a brief overview of recent strategies and emerging trends. Selected examples of complement-related diseases and inhibitor classes are highlighted to illustrate the diversity and creativity in field.

Keywords

Complement Activation Paroxysmal Nocturnal Hemoglobinuria Complement Inhibitor Atypical Hemolytic Uremic Syndrome Paroxysmal Nocturnal Hemoglobinuria Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Dr. Robert A. DeAngelis for critically reading the manuscript. This work was supported by National Institutes of Health grants AI068730, AI030040, AI072106, AI071028, AI097805, DE021685, GM97747, and EY020633.

Disclosure

J.D.L. is the inventor of the C3 inhibitor compstatin and holds several patents about the development and clinical application of compstatin analogs. He has previously served as a member on the Scienepsic Advisory Board of Potentia Pharmaceuticals and is the founder of Amyndas Biotherapeutics, which perform clinical development of compstatin analogs for various indications.

References

  1. Ahmad M, Pyaram K, Mullick J, Sahu A (2007) Viral complement regulators: the expert mimicking swindlers. Indian J Biochem Biophys 44(5):331–343PubMedGoogle Scholar
  2. Alcorlo M, Martinez-Barricarte R, Fernandez FJ, Rodriguez-Gallego C, Round A, Vega MC et al (2011) Unique structure of iC3b resolved at a resolution of 24 A by 3D-electron microscopy. Proc Natl Acad Sci USA 108(32):13236–13240CrossRefGoogle Scholar
  3. Alexion (2011) Soliris® (eculizumab) Approved by FDA for All Patients with Atypical Hemolytic Uremic Syndrome (aHUS). Alexion Pharmaceuticals Press ReleaseGoogle Scholar
  4. Alfinito F, Ruggiero G, Sica M, Udhayachandran A, Rubino V, Pepa RD et al (2011) Eculizumab treatment modifies the immune profile of PNH patients. Immunobiology 217(7):698–703CrossRefGoogle Scholar
  5. Amara U, Flierl MA, Rittirsch D, Klos A, Chen H, Acker B et al (2010) Molecular intercommunication between the complement and coagulation systems. J Immunol 185(9):5628–5636CrossRefPubMedPubMedCentralGoogle Scholar
  6. Anderson DH, Radeke MJ, Gallo NB, Chapin EA, Johnson PT, Curletti CR et al (2010) The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res 29(2):95–112CrossRefPubMedPubMedCentralGoogle Scholar
  7. Arlaud GJ, Barlow PN, Gaboriaud C, Gros P, Narayana SV (2007) Deciphering complement mechanisms: the contributions of structural biology. Mol Immunol 44(16):3809–3822CrossRefGoogle Scholar
  8. Asgari E, Zhou W, Sacks S (2010) Complement in organ transplantation. Curr Opin Organ Transplant 15(4):486–491CrossRefGoogle Scholar
  9. Banda NK, Levitt B, Glogowska MJ, Thurman JM, Takahashi K, Stahl GL et al (2009) Targeted inhibition of the complement alternative pathway with complement receptor 2 and factor H attenuates collagen antibody-induced arthritis in mice. J Immunol 183(9):5928–5937CrossRefPubMedPubMedCentralGoogle Scholar
  10. Banz Y, Rieben R (2012) Role of complement and perspectives for intervention in ischemia-reperfusion damage. Ann Med 44(3):205–217CrossRefGoogle Scholar
  11. Banz Y, Hess OM, Robson SC, Csizmadia E, Mettler D, Meier P et al (2007) Attenuation of myocardial reperfusion injury in pigs by Mirococept, a membrane-targeted complement inhibitor derived from human CR1. Cardiovasc Res 76(3):482–493CrossRefGoogle Scholar
  12. Barratt-Due A, Thorgersen EB, Lindstad JK, Pharo A, Lissina O, Lambris JD et al (2011) Ornithodoros moubata complement inhibitor is an equally effective C5 inhibitor in pigs and humans. J Immunol 187(9):4913–4919CrossRefPubMedPubMedCentralGoogle Scholar
  13. Beinrohr L, Dobo J, Zavodszky P, Gal P (2008) C1, MBL-MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation. Trends Mol Med 14(12):511–521CrossRefGoogle Scholar
  14. Berger J (1974) Complement deposition in the kidney. Adv Nephrol Necker Hosp 4:37–48PubMedGoogle Scholar
  15. Blonder J, Issaq HJ, Veenstra TD (2011) Proteomic biomarker discovery: it’s more than just mass spectrometry. Electrophoresis 32(13):1541–1548PubMedGoogle Scholar
  16. Bora NS, Jha P, Lyzogubov VV, Kaliappan S, Liu J, Tytarenko RG et al (2010) Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice. J Biol Chem 285(44):33826–33833CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bosmann M, Ward PA (2012) Role of C3, C5 and anaphylatoxin receptors in acute lung injury and in sepsis. Adv Exp Med Biol 946:147–159CrossRefPubMedPubMedCentralGoogle Scholar
  18. Brodbeck RM, Cortright DN, Kieltyka AP, Yu J, Baltazar CO, Buck ME et al (2008) Idenepsication and characterization of NDT 9513727 [N, N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanam ine], a novel, orally bioavailable C5a receptor inverse agonist. J Pharmacol Exp Ther 327(3):898–909CrossRefGoogle Scholar
  19. Brown KM, Sacks SH, Sheerin NS (2007) Mechanisms of disease: the complement system in renal injury – new ways of looking at an old foe. Nat Clin Pract Nephrol 3(5):277–286CrossRefGoogle Scholar
  20. Carroll MV, Sim RB (2011) Complement in health and disease. Adv Drug Deliv Rev 63(12):965–975CrossRefGoogle Scholar
  21. Cashman SM, Ramo K, Kumar-Singh R (2011) A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration. PLoS One 6(4):e19078CrossRefPubMedPubMedCentralGoogle Scholar
  22. Chavakis T, Preissner KT, Herrmann M (2007) The anti-inflammatory activities of Staphylococcus aureus. Trends Immunol 28(9):408–418CrossRefGoogle Scholar
  23. Chen Song S, Zhong S, Xiang Y, Li JH, Guo H, Wang WY et al (2011) Complement inhibition enables renal allograft accommodation and long-term engraftment in presensitized nonhuman primates. Am J Transplant 11(10):2057–2066CrossRefGoogle Scholar
  24. Chen H, Ricklin D, Hammel M, Garcia BL, McWhorter WJ, Sfyroera G et al (2010) Allosteric inhibition of complement function by a staphylococcal immune evasion protein. Proc Natl Acad Sci USA 107(41):17621–17626CrossRefGoogle Scholar
  25. Chi ZL, Yoshida T, Lambris JD, Iwata T (2010) Suppression of drusen formation by compstatin, a peptide inhibitor of complement C3 activation, on cynomolgus monkey with early-onset macular degeneration. Adv Exp Med Biol 703:127–135CrossRefPubMedPubMedCentralGoogle Scholar
  26. Christiansen D, Brekke OL, Stenvik J, Lambris JD, Espevik T, Mollnes TE (2012) Differential effect of inhibiting MD-2 and CD14 on LPS- versus whole E. coli bacteria-induced cytokine responses in human blood. Adv Exp Med Biol 946:237–251CrossRefGoogle Scholar
  27. Davis AE 3rd, Lu F, Mejia P (2010) C1 inhibitor, a multi-functional serine protease inhibitor. Thromb Haemost 104(5):886–893PubMedGoogle Scholar
  28. Degn SE, Jensenius JC, Thiel S (2011) Disease-causing mutations in genes of the complement system. Am J Hum Gen 88(6):689–705PubMedGoogle Scholar
  29. Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R (2008) FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist 13(9):993–1000CrossRefGoogle Scholar
  30. Ekdahl KN, Lambris JD, Elwing H, Ricklin D, Nilsson PH, Teramura Y et al (2011) Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies. Adv Drug Deliv Rev 63(12):1042–1050CrossRefPubMedPubMedCentralGoogle Scholar
  31. Engstrom G, Hedblad B, Janzon L, Lindgarde F (2007) Complement C3 and C4 in plasma and incidence of myocardial infarction and stroke: a population-based cohort study. Eur J Cardiovasc Prev Rehabil 14(3):392–397CrossRefGoogle Scholar
  32. Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD, LaFerla FM et al (2009) Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol 183(2):1375–1383CrossRefPubMedPubMedCentralGoogle Scholar
  33. Fonseca MI, Chu SH, Berci AM, Benoit ME, Peters DG, Kimura Y et al (2011) Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer’s disease. J Neuroinflammation 8(1):4CrossRefPubMedPubMedCentralGoogle Scholar
  34. Forneris F, Ricklin D, Wu J, Tzekou A, Wallace RS, Lambris JD et al (2010) Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 330(6012):1816–1820CrossRefPubMedPubMedCentralGoogle Scholar
  35. Fraser DA, Harris CL, Williams AS, Mizuno M, Gallagher S, Smith RA et al (2003) Generation of a recombinant, membrane-targeted form of the complement regulator CD59: activity in vitro and in vivo. J Biol Chem 278(49):48921–48927CrossRefGoogle Scholar
  36. Fridkis-Hareli M, Storek M, Mazsaroff I, Risitano AM, Lundberg AS, Horvath CJ et al (2011) Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway-mediated diseases. Blood 118(17):4705–4713CrossRefPubMedPubMedCentralGoogle Scholar
  37. Fritzinger DC, Dean R, Meschter C, Wong K, Halter R, Borlak J et al (2010) Complement depletion with humanized cobra venom factor in a mouse model of age-related macular degeneration. Adv Exp Med Biol 703:151–162CrossRefGoogle Scholar
  38. Fujita E, Farkas I, Campbell W, Baranyi L, Okada H, Okada N (2004) Inactivation of C5a anaphylatoxin by a peptide that is complementary to a region of C5a. J Immunol 172(10):6382–6387CrossRefGoogle Scholar
  39. Fujiwara I, Nakajima H, Akioka K, Matsuda T, Oka T (1997) Soluble complement receptor type 1 and antithrombin-III combination therapy prolongs xenograft survival: the role of thrombin and prostacyclin in hyperacute rejection. Transplant Proc 29(1–2):935–937CrossRefGoogle Scholar
  40. Garlatti V, Chouquet A, Lunardi T, Vives R, Paidassi H, Lortat-Jacob H et al (2010) Cutting edge: C1q binds deoxyribose and heparan sulfate through neighboring sites of its recognition domain. J Immunol 185(2):808–812CrossRefGoogle Scholar
  41. Ge X, Wu L, Hu W, Fernandes S, Wang C, Li X et al (2011) rILYd4, a human CD59 inhibitor, enhances complement-dependent cytotoxicity of ofatumumab against rituximab-resistant B-cell lymphoma cells and chronic lymphocytic leukemia. Clin Cancer Res 17(21):6702–6711CrossRefPubMedPubMedCentralGoogle Scholar
  42. Geis N, Zell S, Rutz R, Li W, Giese T, Mamidi S et al (2010) Inhibition of membrane complement inhibitor expression (CD46, CD55, CD59) by siRNA sensitizes tumor cells to complement attack in vitro. Curr Cancer Drug Targets 10(8):922–931CrossRefGoogle Scholar
  43. Ghebremariam YT, Engelbrecht G, Tyler M, Lotz Z, Govender D, Kotwal GJ et al (2010) Vaccinia virus complement control protein (VCP) improves kidney structure and function following ischemia/reperfusion injury in rats. J Surg Res 159(2):747–754CrossRefGoogle Scholar
  44. Gibson J, Hakobyan S, Cree AJ, Collins A, Harris CL, Ennis S et al (2012) Variation in complement component C1 inhibitor in age-related macular degeneration. Immunobiology 217(2):251–255CrossRefGoogle Scholar
  45. Gingras AR, Girija UV, Keeble AH, Panchal R, Mitchell DA, Moody PC et al (2011) Structural basis of mannan-binding lectin recognition by its associated serine protease MASP-1: implications for complement activation. Structure 19(11):1635–1643CrossRefGoogle Scholar
  46. Gold L, Ayers D, Bertino J, Bock C, Bock A, Brody EN et al (2010) Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One 5(12):e15004CrossRefPubMedPubMedCentralGoogle Scholar
  47. Gombos T, Forhecz Z, Pozsonyi Z, Szeplaki G, Kunde J, Fust G et al (2012) Complement anaphylatoxin C3a as a novel independent prognostic marker in heart failure. Clin Res Cardiol. doi:10.1007/s00392-012-0432-6Google Scholar
  48. Gompels MM, Lock RJ (2011) Cinryze (C1-inhibitor) for the treatment of hereditary angioedema. Expert Rev Clin Immunol 7(5):569–573CrossRefGoogle Scholar
  49. Gustafsson E, Forsberg C, Haraldsson K, Lindman S, Ljung L, Furebring C (2009) Purification of truncated and mutated chemotaxis inhibitory protein of Staphylococcus aureus – an anti-inflammatory protein. Protein Expr Purif 63(2):95–101CrossRefGoogle Scholar
  50. Hadders MA, Bubeck D, Roversi P, Hakobyan S, Forneris F, Morgan BP et al (2012) Assembly and regulation of the membrane attack complex based on structures of C5b6 and sC5b9. Cell Rep 1:1–8CrossRefGoogle Scholar
  51. Halili MA, Ruiz-Gomez G, Le GT, Abbenante G, Fairlie DP (2009) Complement component C2, inhibiting a latent serine protease in the classical pathway of complement activation. Biochemistry 48(35):8466–8472CrossRefGoogle Scholar
  52. Hamilton G, Evans KL, Macintyre DJ, Deary IJ, Dominiczak A, Smith BH et al (2012) Alzheimer’s disease risk factor complement receptor 1 is associated with depression. Neurosci Lett 510(1):6–9CrossRefGoogle Scholar
  53. Hecker LA, Edwards AO, Ryu E, Tosakulwong N, Baratz KH, Brown WL et al (2010) Genetic control of the alternative pathway of complement in humans and age-related macular degeneration. Hum Mol Genet 19(1):209–215CrossRefGoogle Scholar
  54. Hepburn NJ, Williams AS, Nunn MA, Chamberlain-Banoub JC, Hamer J, Morgan BP et al (2007) In vivo characterization and therapeutic efficacy of a C5-specific inhibitor from the soft tick Ornithodoros moubata. J Biol Chem 282(11):8292–8299CrossRefGoogle Scholar
  55. Heurich M, Martinez-Barricarte R, Francis NJ, Roberts DL, Rodriguez de Cordoba S, Morgan BP et al (2011) Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc Natl Acad Sci USA 108(21):8761–8766CrossRefGoogle Scholar
  56. Huang Y, Qiao F, Atkinson C, Holers VM, Tomlinson S (2008) A novel targeted inhibitor of the alternative pathway of complement and its therapeutic application in ischemia/reperfusion injury. J Immunol 181(11):8068–8076CrossRefPubMedPubMedCentralGoogle Scholar
  57. Igonin AA, Protsenko DN, Galstyan GM, Vlasenko AV, Khachatryan NN, Nekhaev IV et al (2011) C1-esterase inhibitor infusion increases survival rates for patients with sepsis. Crit Care Med 40:770–777CrossRefGoogle Scholar
  58. Janssen BJ, Huizinga EG, Raaijmakers HC, Roos A, Daha MR, Nilsson-Ekdahl K et al (2005) Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437(7058):505–511CrossRefPubMedPubMedCentralGoogle Scholar
  59. Janssen BJ, Christodoulidou A, McCarthy A, Lambris JD, Gros P (2006) Structure of C3b reveals conformational changes that underlie complement activity. Nature 444(7116):213–216CrossRefPubMedPubMedCentralGoogle Scholar
  60. Kajander T, Lehtinen MJ, Hyvarinen S, Bhattacharjee A, Leung E, Isenman DE et al (2011) Dual interaction of factor H with C3d and glycosaminoglycans in host-nonhost discrimination by complement. Proc Natl Acad Sci USA 108(7):2897–2902CrossRefGoogle Scholar
  61. Kato M, Morozumi K, Takeuchi O, Oikawa T, Koyama K, Usami T et al (2003) Complement fragment C4d deposition in peritubular capillaries in acute humoral rejection after ABO blood group-incompatible human kidney transplantation. Transplantation 75(5):663–665CrossRefGoogle Scholar
  62. Keating GM (2009) Human C1-esterase inhibitor concentrate (Berinert). BioDrugs 23(6):399–406CrossRefGoogle Scholar
  63. Khan MA, Jiang X, Dhillon G, Beilke J, Holers VM, Atkinson C et al (2011) CD4+ T cells and complement independently mediate graft ischemia in the rejection of mouse orthotopic tracheal transplants. Circ Res 109(11):1290–1301CrossRefPubMedPubMedCentralGoogle Scholar
  64. Kirschfink M, Mollnes TE (2001) C1-inhibitor: an anti-inflammatory reagent with therapeutic potential. Expert Opin Pharmacother 2(7):1073–1083CrossRefGoogle Scholar
  65. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J (2009) The role of the anaphylatoxins in health and disease. Mol Immunol 46(14):2753–2766CrossRefPubMedPubMedCentralGoogle Scholar
  66. Kocsis A, Kekesi KA, Szasz R, Vegh BM, Balczer J, Dobo J et al (2010) Selective inhibition of the lectin pathway of complement with phage display selected peptides against mannose-binding lectin-associated serine protease (MASP)-1 and -2: significant contribution of MASP-1 to lectin pathway activation. J Immunol 185(7):4169–4178CrossRefGoogle Scholar
  67. Kohl J (2006) Drug evaluation: the C5a receptor antagonist PMX-53. Curr Opin Mol Ther 8(6):529–538PubMedGoogle Scholar
  68. Kollessery G, Nordgren TM, Mittal AK, Joshi SS, Sanderson SD (2011) Tumor-specific peptide-based vaccines containing the conformationally biased, response-selective C5a agonists EP54 and EP67 protect against aggressive large B cell lymphoma in a syngeneic murine model. Vaccine 29(35):5904–5910CrossRefGoogle Scholar
  69. Kourtzelis I, Markiewski MM, Doumas M, Rafail S, Kambas K, Mitroulis I et al (2010) Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 116(4):631–639CrossRefPubMedPubMedCentralGoogle Scholar
  70. Kraemer S, Vaught JD, Bock C, Gold L, Katilius E, Keeney TR et al (2011) From SOMAmer-based biomarker discovery to diagnostic and clinical applications: a SOMAmer-based, streamlined multiplex proteomic assay. PLoS One 6(10):e26332CrossRefPubMedPubMedCentralGoogle Scholar
  71. Kulkarni AP, Govender DA, Kotwal GJ, Kellaway LA (2011) Modulation of anxiety behavior by intranasally administered vaccinia virus complement control protein and curcumin in a mouse model of Alzheimer’s disease. Curr Alzheimer Res 8(1):95–113CrossRefGoogle Scholar
  72. Laarman A, Milder F, van Strijp J, Rooijakkers S (2010) Complement inhibition by gram-positive pathogens: molecular mechanisms and therapeutic implications. J Mol Med (Berlin) 88(2):115–120CrossRefGoogle Scholar
  73. Lachmann PJ, Smith RA (2009) Taking complement to the clinic – has the time finally come? Scand J Immunol 69(6):471–478CrossRefGoogle Scholar
  74. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M et al (2009) Genome-wide association study idenepsies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099CrossRefGoogle Scholar
  75. Lambris JD, Ricklin D, Geisbrecht BV (2008) Complement evasion by human pathogens. Nat Rev Microbiol 6(2):132–142CrossRefPubMedPubMedCentralGoogle Scholar
  76. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M et al. (2011) Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 364(26):2561–2563CrossRefGoogle Scholar
  77. Laursen L (2011) E. coli crisis opens door for Alexion drug trial. Nat Biotechnol 29(8):671CrossRefGoogle Scholar
  78. Laursen NS, Gordon N, Hermans S, Lorenz N, Jackson N, Wines B et al (2010) Structural basis for inhibition of complement C5 by the SSL7 protein from Staphylococcus aureus. Proc Natl Acad Sci USA 107(8):3681–3686CrossRefGoogle Scholar
  79. Laursen NS, Andersen KR, Braren I, Spillner E, Sottrup-Jensen L, Andersen GR (2011) Substrate recognition by complement convertases revealed in the C5-cobra venom factor complex. EMBO J 30(3):606–616CrossRefPubMedPubMedCentralGoogle Scholar
  80. Lazar HL, Keilani T, Fitzgerald CA, Shapira OM, Hunter CT, Shemin RJ et al (2007) Beneficial effects of complement inhibition with soluble complement receptor 1 (TP10) during cardiac surgery: is there a gender difference? Circulation 116(11 Suppl):I83–I88PubMedGoogle Scholar
  81. Lewis AG, Kohl G, Ma Q, Devarajan P, Kohl J (2008) Pharmacological targeting of C5a receptors during organ preservation improves kidney graft survival. Clin Exp Immunol 153(1):117–126CrossRefPubMedPubMedCentralGoogle Scholar
  82. Li JS, Jaggers J, Anderson PA (2006) The use of TP10, soluble complement receptor 1, in cardiopulmonary bypass. Expert Rev Cardiovasc Ther 4(5):649–654CrossRefGoogle Scholar
  83. Licht C, Weyersberg A, Heinen S, Stapenhorst L, Devenge J, Beck B et al (2005) Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis 45(2):415–421CrossRefGoogle Scholar
  84. Luzzatto L, Risitano AM, Notaro R (2010) Paroxysmal nocturnal hemoglobinuria and eculizumab. Haematologica 95(4):523–526CrossRefPubMedPubMedCentralGoogle Scholar
  85. Lynch AM, Gibbs RS, Murphy JR, Byers T, Neville MC, Giclas PC et al (2008) Complement activation fragment Bb in early pregnancy and spontaneous preterm birth. Am J Obstet Gynecol 199(4):354 e1–8CrossRefGoogle Scholar
  86. Lynch AM, Gibbs RS, Murphy JR, Giclas PC, Salmon JE, Holers VM (2011) Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes. Obstet Gynecol 117(1):75–83CrossRefPubMedPubMedCentralGoogle Scholar
  87. Markiewski MM, Lambris JD (2009) Is complement good or bad for cancer patients? A new perspective on an old dilemma. Trends Immunol 30(6):286–292CrossRefPubMedPubMedCentralGoogle Scholar
  88. Markiewski MM, DeAngelis RA, Benencia F, Ricklin-Lichtsteiner SK, Koutoulaki A, Gerard C et al (2008) Modulation of the antitumor immune response by complement. Nat Immunol 9(11):1225–1235CrossRefPubMedPubMedCentralGoogle Scholar
  89. Mathieu MC, Sawyer N, Greig GM, Hamel M, Kargman S, Ducharme Y et al (2005) The C3a receptor antagonist SB 290157 has agonist activity. Immunol Lett 100(2):139–145CrossRefGoogle Scholar
  90. Monk PN, Scola AM, Madala P, Fairlie DP (2007) Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol 152(4):429–448CrossRefPubMedPubMedCentralGoogle Scholar
  91. Morgan HP, Schmidt CQ, Guariento M, Blaum BS, Gillespie D, Herbert AP et al (2011) Structural basis for engagement by complement factor H of C3b on a self surface. Nat Struct Mol Biol 18(4):463–470CrossRefPubMedPubMedCentralGoogle Scholar
  92. Mosca T, Menezes MC, Dionigi PC, Stirbulov R, Forte WC (2011) C3 and C4 complement system components as biomarkers in the intermittent atopic asthma diagnosis. J Pediatr (Rio de Janeiro) 87(6):512–516Google Scholar
  93. Mullard A (2012) Protein–protein interaction inhibitors get into the groove. Nat Rev Drug Discov 11(3):173–175CrossRefGoogle Scholar
  94. Nagar B, Jones RG, Diefenbach RJ, Isenman DE, Rini JM (1998) X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2. Science 280(5367):1277–1281CrossRefPubMedPubMedCentralGoogle Scholar
  95. Nilsson B, Nilsson UR, Karlsson-Parra A, Sjolin-Forsberg G, Hallgren R (1994) Reconstitution of the alternative pathway of complement by plasma infusions given to a patient with an SLE-like syndrome associated with a hereditary C3 dysfunction. Ann Rheum Dis 53(10):691–694CrossRefPubMedPubMedCentralGoogle Scholar
  96. Nilsson B, Korsgren O, Lambris JD, Ekdahl KN (2010) Can cells and biomaterials in therapeutic medicine be shielded from innate immune recognition? Trends Immunol 31(1):32–38CrossRefPubMedPubMedCentralGoogle Scholar
  97. Nunn MA, Sharma A, Paesen GC, Adamson S, Lissina O, Willis AC et al (2005) Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. J Immunol 174(4):2084–2091CrossRefGoogle Scholar
  98. Nurnberger J, Philipp T, Witzke O, Opazo Saez A, Vester U, Baba HA et al (2009) Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 360(5):542–544CrossRefGoogle Scholar
  99. Oikonomopoulou K, Ricklin D, Ward PA, Lambris JD (2012) Interactions between coagulation and complement – their role in inflammation. Semin Immunopathol 34(1):151–165CrossRefGoogle Scholar
  100. Otto M, Hawlisch H, Monk PN, Muller M, Klos A, Karp CL et al (2004) C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism. J Biol Chem 279(1):142–151CrossRefGoogle Scholar
  101. Palikhe A, Sinisalo J, Seppanen M, Haario H, Meri S, Valtonen V et al (2007) Serum complement C3/C4 ratio, a novel marker for recurrent cardiovascular events. Am J Cardiol 99(7):890–895CrossRefPubMedPubMedCentralGoogle Scholar
  102. Parker CJ (2012) Paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol 19(3):141–148CrossRefPubMedPubMedCentralGoogle Scholar
  103. Patel H, Smith RA, Sacks SH, Zhou W (2006) Therapeutic strategy with a membrane-localizing complement regulator to increase the number of usable donor organs after prolonged cold storage. J Am Soc Nephrol 17(4):1102–1111CrossRefPubMedPubMedCentralGoogle Scholar
  104. Perkins SJ, Gilbert HE, Aslam M, Hannan J, Holers VM, Goodship TH (2002) Solution structures of complement components by X-ray and neutron scattering and analytical ultracentrifugation. Biochem Soc Trans 30(Pt 6):996–1001CrossRefGoogle Scholar
  105. Perkins SJ, Gilbert HE, Aslam M, Hannan J, Holers VM, Goodship TH (2002) Solution structures of complement components by X-ray and neutron scattering and analytical ultracentrifugation. Biochem Soc Trans 30(Pt 6):996–1001CrossRefGoogle Scholar
  106. Proitsi P, Lupton MK, Dudbridge F, Tsolaki M, Hamilton G, Daniilidou M et al (2012) Alzheimer’s disease and age-related macular degeneration have different genetic models for complement gene variation. Neurobiol Aging 33(8):1843.e9-1843.e17CrossRefGoogle Scholar
  107. Qu H, Ricklin D, Bai H, Chen H, Reis ES, Maciejewski M, Tzekou A, DeAngelis RA, Resuello RRG, Lupu F, Barlow PN, Lambris JD (2012) New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology (in press). doi:10.1016/j.imbio.2012.06.003CrossRefPubMedPubMedCentralGoogle Scholar
  108. Qu H, Ricklin D, Lambris JD (2009) Recent developments in low molecular weight complement inhibitors. Mol Immunol 47(2–3):185–195CrossRefPubMedPubMedCentralGoogle Scholar
  109. Qu H, Magotti P, Ricklin D, Wu EL, Kourtzelis I, Wu YQ et al (2011) Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potency. Mol Immunol 48(4):481–489CrossRefGoogle Scholar
  110. Ramos-Casals M, Campoamor MT, Chamorro A, Salvador G, Segura S, Botero JC et al (2004) Hypocomplementemia in systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence and clinical significance in 667 patients. Lupus 13(10):777–783CrossRefPubMedPubMedCentralGoogle Scholar
  111. Recknagel S, Bindl R, Kurz J, Wehner T, Schoengraf P, Ehrnthaller C et al (2012) C5aR-antagonist significantly reduces the deleterious effect of a blunt chest trauma on fracture healing. J Orthop Res 30(4):581–586CrossRefPubMedPubMedCentralGoogle Scholar
  112. Reis SE, Falcao DA, Isaac L (2006) Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H. Scand J Immunol 63(3):155–168CrossRefGoogle Scholar
  113. Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM (2009) Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes. Invest Ophthalmol Vis Sci 50(12):5818–5827CrossRefPubMedPubMedCentralGoogle Scholar
  114. Ricklin D, Lambris JD (2007a) Complement-targeted therapeutics. Nat Biotechnol 25(11):1265–1275CrossRefPubMedPubMedCentralGoogle Scholar
  115. Ricklin D, Lambris JD (2007b) Exploring the complement interaction network using surface plasmon resonance. Adv Exp Med Biol 598:260–278CrossRefGoogle Scholar
  116. Ricklin D, Lambris JD (2008) Compstatin: a complement inhibitor on its way to clinical application. Adv Exp Med Biol 632:273–292PubMedPubMedCentralGoogle Scholar
  117. Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11(9):785–797CrossRefPubMedPubMedCentralGoogle Scholar
  118. Risitano AM, Perna F, Selleri C (2011) Achievements and limitations of complement inhibition by eculizumab in paroxysmal nocturnal hemoglobinuria: the role of complement component 3. Mini Rev Med Chem 11(6):528–535CrossRefGoogle Scholar
  119. Rodriguez de Cordoba S, Harris CL, Morgan BP, Llorca O (2011) Lessons from functional and structural analyses of disease-associated genetic variants in the complement alternative pathway. Biochim Biophys Acta 1812(1):12–22CrossRefGoogle Scholar
  120. Rohrer B, Long Q, Coughlin B, Renner B, Huang Y, Kunchithapautham K et al (2010) A targeted inhibitor of the complement alternative pathway reduces RPE injury and angiogenesis in models of age-related macular degeneration. Adv Exp Med Biol 703:137–149CrossRefPubMedPubMedCentralGoogle Scholar
  121. Rohrer B, Coughlin B, Bandyopadhyay M, Holers VM (2012) Systemic human CR2-targeted complement alternative pathway inhibitor ameliorates mouse laser-induced choroidal neovascularization. J Ocul Pharmacol Ther. doi:10.1089/jop.2011.0212Google Scholar
  122. Rooijakkers SH, Wu J, Ruyken M, van Domselaar R, Planken KL, Tzekou A et al (2009) Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat Immunol 10(7):721–727CrossRefPubMedPubMedCentralGoogle Scholar
  123. Roth A, Hock C, Konik A, Christoph S, Duhrsen U (2011) Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. Int J Hematol 93(6):704–714CrossRefGoogle Scholar
  124. Roversi P, Lissina O, Johnson S, Ahmat N, Paesen GC, Ploss K et al (2007) The structure of OMCI, a novel lipocalin inhibitor of the complement system. J Mol Biol 369(3):784–793CrossRefPubMedPubMedCentralGoogle Scholar
  125. Ruiz-Gomez G, Lim J, Halili MA, Le GT, Madala PK, Abbenante G et al (2009) Structure-activity relationships for substrate-based inhibitors of human complement factor B. J Med Chem 52(19):6042–6052CrossRefGoogle Scholar
  126. Sacks SH, Zhou W (2012) The role of complement in the early response to transplantation. Nat Rev Immunol 12(6):431–442Google Scholar
  127. Sahu A, Kay BK, Lambris JD (1996) Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J Immunol 157(2):884–891Google Scholar
  128. Sample I (2010) Mirococept could double life of transplant organs. The Guardian 2010. http://www.guardian.co.uk/science/2010/sep/15/mirococept-transplant-organs
  129. Sanchez-Carbayo M (2011) Antibody microarrays as tools for biomarker discovery. Methods Mol Biol 785:159–182CrossRefGoogle Scholar
  130. Schmid RA, Hillinger S, Hamacher J, Stammberger U (2001) TP20 is superior to TP10 in reducing ischemia/reperfusion injury in rat lung grafts. Transplant Proc 33(1–2):948–949CrossRefGoogle Scholar
  131. Schmidt CQ, Bai H, Risitano AM, Barlow PN, Ricklin D, Lambris JD (2012) Rational engineering of a novel complement regulator affords double targeting of host cells and controls innate immunity in disease condition (submitted)Google Scholar
  132. Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Borncke F et al (2008) Systemic complement activation in age-related macular degeneration. PLoS One 3(7):e2593CrossRefPubMedPubMedCentralGoogle Scholar
  133. Schuster MC, Chen H, Lambris JD (2007) Hydrogen/deuterium exchange mass spectrometry: potential for investigating innate immunity proteins. Adv Exp Med Biol 598:407–417CrossRefGoogle Scholar
  134. Schuster MC, Ricklin D, Papp K, Molnar KS, Coales SJ, Hamuro Y et al (2008) Dynamic structural changes during complement C3 activation analyzed by hydrogen/deuterium exchange mass spectrometry. Mol Immunol 45(11):3142–3151CrossRefPubMedPubMedCentralGoogle Scholar
  135. Serkova NJ, Renner B, Larsen BA, Stoldt CR, Hasebroock KM, Bradshaw-Pierce EL et al (2010) Renal inflammation: targeted iron oxide nanoparticles for molecular MR imaging in mice. Radiology 255(2):517–526CrossRefPubMedPubMedCentralGoogle Scholar
  136. Shaw CD, Storek MJ, Young KA, Kovacs JM, Thurman JM, Holers VM et al (2010) Delineation of the complement receptor type 2-C3d complex by site-directed mutagenesis and molecular docking. J Mol Biol 404(4):697–710CrossRefGoogle Scholar
  137. Silasi-Mansat R, Zhu H, Popescu NI, Peer G, Sfyroera G, Magotti P et al (2010) Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116(6):1002–1010CrossRefPubMedPubMedCentralGoogle Scholar
  138. Sirmaci A, Walsh T, Akay H, Spiliopoulos M, Sakalar YB, Hasanefendioglu-Bayrak A et al (2010) MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes. Am J Hum Genet 87(5):679–686CrossRefPubMedPubMedCentralGoogle Scholar
  139. Skattum L, Martensson U, Sjoholm AG (1997) Hypocomplementaemia caused by C3 nephritic factors (C3 NeF): clinical findings and the coincidence of C3 NeF type II with anti-C1q autoantibodies. J Intern Med 242(6):455–464CrossRefGoogle Scholar
  140. Skattum L, van Deuren M, van der Poll T, Truedsson L (2011) Complement deficiency states and associated infections. Mol Immunol 48(14):1643–1655CrossRefGoogle Scholar
  141. Smith RA (2002) Targeting anticomplement agents. Biochem Soc Trans 30(Pt 6):1037–1041CrossRefGoogle Scholar
  142. Smith GP, Smith RA (2001) Membrane-targeted complement inhibitors. Mol Immunol 38(2–3):249–255CrossRefGoogle Scholar
  143. Sokolov A, Hellerud BC, Lambris JD, Johannessen EA, Mollnes TE (2011) Activation of polymorphonuclear leukocytes by candidate biomaterials for an implantable glucose sensor. J Diabetes Sci Technol 5(6):1490–1498CrossRefPubMedPubMedCentralGoogle Scholar
  144. Souza DG, Esser D, Bradford R, Vieira AT, Teixeira MM (2005) APT070 (Mirococept), a membrane-localised complement inhibitor, inhibits inflammatory responses that follow intestinal ischaemia and reperfusion injury. Br J Pharmacol 145(8):1027–1034CrossRefPubMedPubMedCentralGoogle Scholar
  145. Spitzer D, Unsinger J, Bessler M, Atkinson JP (2004) ScFv-mediated in vivo targeting of DAF to erythrocytes inhibits lysis by complement. Mol Immunol 40(13):911–919CrossRefGoogle Scholar
  146. Spitzer D, Unsinger J, Mao D, Wu X, Molina H, Atkinson JP (2005) In vivo correction of complement regulatory protein deficiency with an inhibitor targeting the red blood cell membrane. J Immunol 175(11):7763–7770CrossRefPubMedPubMedCentralGoogle Scholar
  147. Szalai AJ, Digerness SB, Agrawal A, Kearney JF, Bucy RP, Niwas S et al (2000) The Arthus reaction in rodents: species-specific requirement of complement. J Immunol 164(1):463–468CrossRefGoogle Scholar
  148. Thorgersen EB, Ludviksen JK, Lambris JD, Sfyroera G, Nielsen EW, Mollnes TE (2010) Anti-inflammatory effects of C1-Inhibitor in porcine and human whole blood are independent of its protease inhibition activity. Innate Immun 16(4):254–264CrossRefGoogle Scholar
  149. Tillou X, Poirier N, Le Bas-Bernardet S, Hervouet J, Minault D, Renaudin K et al (2010) Recombinant human C1-inhibitor prevents acute antibody-mediated rejection in alloimmunized baboons. Kidney Int 78(2):152–159CrossRefGoogle Scholar
  150. Tokodai K, Goto M, Inagaki A, Nakanishi W, Ogawa N, Satoh K et al (2010) Attenuation of cross-talk between the complement and coagulation cascades by C5a blockade improves early outcomes after intraportal islet transplantation. Transplantation 90(12):1358–1365CrossRefGoogle Scholar
  151. Torreira E, Tortajada A, Montes T, Rodriguez de Cordoba S, Llorca O (2009) 3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase. Proc Natl Acad Sci USA 106(3):882–887CrossRefGoogle Scholar
  152. Tourangeau LM, Zuraw BL (2011) The new era of C1-esterase inhibitor deficiency therapy. Curr Allergy Asthma Rep 11(5):345–351CrossRefGoogle Scholar
  153. Tschumi S, Gugger M, Bucher BS, Riedl M, Simonetti GD (2011) Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings. Pediatr Nephrol 26(11):2085–2088CrossRefGoogle Scholar
  154. van den Elsen JM, Isenman DE (2011) A crystal structure of the complex between human complement receptor 2 and its ligand C3d. Science 332(6029):608–611CrossRefPubMedPubMedCentralGoogle Scholar
  155. van der Pals J, Koul S, Andersson P, Gotberg M, Ubachs JF, Kanski M et al (2010) Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model. BMC Cardiovasc Disord 10:45CrossRefPubMedPubMedCentralGoogle Scholar
  156. Veerhuis R, Nielsen HM, Tenner AJ (2011) Complement in the brain. Mol Immunol 48(14):1592–1603CrossRefPubMedPubMedCentralGoogle Scholar
  157. Vogel CW, Fritzinger DC (2010) Cobra venom factor: structure, function, and humanization for therapeutic complement depletion. Toxicon 56(7):1198–1222CrossRefGoogle Scholar
  158. Waters AM, Licht C (2011) aHUS caused by complement dysregulation: new therapies on the horizon. Pediatr Nephrol 26(1):41–57CrossRefGoogle Scholar
  159. Wells JA, McClendon CL (2007) Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450(7172):1001–1009CrossRefGoogle Scholar
  160. Wiesmann C, Katschke KJ, Yin J, Helmy KY, Steffek M, Fairbrother WJ et al (2006) Structure of C3b in complex with CRIg gives insights into regulation of complement activation. Nature 444(7116):217–220CrossRefPubMedPubMedCentralGoogle Scholar
  161. Woodruff TM, Nandakumar KS, Tedesco F (2011) Inhibiting the C5-C5a receptor axis. Mol Immunol 48(14): 1631–1642CrossRefPubMedPubMedCentralGoogle Scholar
  162. Wu J, Wu YQ, Ricklin D, Janssen BJ, Lambris JD, Gros P (2009) Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat Immunol 10(7):728–733CrossRefPubMedPubMedCentralGoogle Scholar
  163. Wu YQ, Qu H, Sfyroera G, Tzekou A, Kay BK, Nilsson B et al (2011) Protection of nonself surfaces from complement attack by factor H-binding peptides: implications for therapeutic medicine. J Immunol 186(7):4269–4277CrossRefPubMedPubMedCentralGoogle Scholar
  164. Yehoshua Z, Rosenfeld PJ, Albini TA (2011) Current clinical trials in dry AMD and the definition of appropriate clinical outcome measures. Semin Ophthalmol 26(3):167–180CrossRefPubMedPubMedCentralGoogle Scholar
  165. Zeerleder S (2011) C1-inhibitor: more than a serine protease inhibitor. Semin Thromb Hemost 37(4):362–374CrossRefGoogle Scholar
  166. Zilow G, Sturm JA, Rother U, Kirschfink M (1990) Complement activation and the prognostic value of C3a in patients at risk of adult respiratory distress syndrome. Clin Exp Immunol 79(2):151–157CrossRefPubMedPubMedCentralGoogle Scholar
  167. Zipfel PF, Lauer NL, Ricklin D, Heinen SH, Dahse HMD, Tzekou A et al (2011) The new chimeric alternative complement inhibitor COMP_CFH15-20 protects surfaces from complement-mediated damage (conference abstract). Mol Immunol 48(14):1713CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineUniversity of PennsylvaniaPhiladelphiaUSA

Personalised recommendations