New milestones ahead in complement-targeted therapy

Seminars in Immunology

Volumn 28, Issue 3, 2016, Pages 208-222

  Ricklin, Daniel ^a   Lambris, John D ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Complement; Immune modulation; Inflammation; Therapeutics

Indexed keywords

COMPLEMENT; COMPLEMENT COMPONENT C5 INHIBITOR; COMPLEMENT INHIBITOR; ANTIINFLAMMATORY AGENT;

ARTHRITIS; CANCER IMMUNOTHERAPY; COMPLEMENT ACTIVATION; COMPLEMENT INHIBITION; COMPLEMENT SYSTEM; DEGENERATIVE DISEASE; DRUG DESIGN; DRUG INDICATION; DRUG SAFETY; GENE AMPLIFICATION; HEMATOLOGIC DISEASE; HEMODIALYSIS; HUMAN; IMMUNOMODULATION; IMMUNOTHERAPY; INFECTION; INJURY; KIDNEY DISEASE; MALIGNANT NEOPLASTIC DISEASE; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RARE DISEASE; REVIEW; RISK ASSESSMENT; SIGNAL TRANSDUCTION; TRANSPLANTATION; UNSPECIFIED SIDE EFFECT; ANIMAL; CLINICAL TRIAL (TOPIC); DRUG DEVELOPMENT; EVIDENCE BASED MEDICINE; IMMUNE COMPLEX DISEASE; IMMUNOLOGY; INNATE IMMUNITY; MOLECULARLY TARGETED THERAPY; PRECLINICAL STUDY;

ANIMALS; ANTI-INFLAMMATORY AGENTS; CLINICAL TRIALS AS TOPIC; COMPLEMENT ACTIVATION; COMPLEMENT SYSTEM PROTEINS; DRUG DISCOVERY; DRUG EVALUATION, PRECLINICAL; EVIDENCE-BASED MEDICINE; HUMANS; IMMUNE COMPLEX DISEASES; IMMUNITY, INNATE; MOLECULAR TARGETED THERAPY;

EID: 84991794910     PISSN: 10445323     EISSN: 10963618     Source Type: Journal    
DOI: 10.1016/j.smim.2016.06.001     Document Type: Review

References (138)

1. [1] Baker, B.R., Erickson, E.H., Irreversible enzyme inhibitors: CLII. Proteolytic enzymes. X. Inhibition of guinea pig complement by substituted benzamidines. J. Med. Chem. 12 (1969), 408–414.
2. [2] Muller-Eberhard, H.J., Chemistry and reaction mechanisms of complement. Adv. Immunol. 8 (1968), 1–80.
3. [3] Lachmann, P.J., Smith, R.A., Taking complement to the clinic–has the time finally come? Scand. J. Immunol. 69 (2009), 471–478.
4. [4] Sahu, A., Lambris, J.D., Complement inhibitors: a resurgent concept in anti-inflammatory therapeutics. Immunopharmacology 49 (2000), 133–148.
5. [5] Ricklin, D., Lambris, J.D., Complement-targeted therapeutics. Nat. Biotechnol. 25 (2007), 1265–1275.
6. [6] Morgan, B.P., Complement, Harris C.L., a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 14 (2015), 857–877.
7. [7] Ricklin, D., Lambris, J.D., Complement in immune and inflammatory disorders: therapeutic interventions. J. Immunol. 190 (2013), 3839–3847.
8. [8] Merle, N.S., Church, S.E., Fremeaux-Bacchi, V., Roumenina, L.T., Complement system part I − molecular mechanisms of activation and regulation. Front. Immunol., 6, 2015, 262.
9. [9] Merle, N.S., Noe, R., Halbwachs-Mecarelli, L., Fremeaux-Bacchi, V., Roumenina, L.T., Complement system part II: role in immunity. Front. Immunol., 6, 2015, 257.
10. [10] Ricklin, D., Hajishengallis, G., Yang, K., Lambris, J.D., Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11 (2010), 785–797.
11. [11] Ricklin, D., Lambris, J.D., Complement in immune and inflammatory disorders: pathophysiological mechanisms. J. Immunol. 190 (2013), 3831–3838.
12. [12] Ricklin, D., Reis, E.S., Lambris, J.D., Complement in disease: a defence system turing offensive. Nature Reviews: Nephrology, 2016, 10.1038/nrneph.2016.70.
13. [13] Reis, E.S., Mastellos, D.C., Yancopoulou, D., Risitano, A.M., Ricklin, D., Lambris, J.D., Applying complement therapeutics to rare diseases. Clin. Immunol. 161 (2015), 225–240.
14. [14] Zeerleder, S., C1-inhibitor: more than a serine protease inhibitor. Semin. Thromb. Hemost. 37 (2011), 362–374.
15. ® (C1 esterase inhibitor [human]) Receives FDA Fast Track Designation for Investigation in the Treatment of Antibody Mediated Rejection (AMR) in Patients Receiving Kidney Transplants. [Press Release] Shire. 13 2015 https://www.shire.com/newsroom/2015/october/shires-cinryze (accessed 16.02.16.).
16. [16] True North Therapeutics Receives Orphan Drug Designation in the European Union for TNT009 for the Treatment of Autoimmune Hemolytic Anemia, including Cold Agglutinin Disease (CAD) [Press Release] True North Therapeutics. 25 2016 http://www.truenorthrx.com/news-events/press-releases/true-north-therapeutics-receives-orphan-drug-designation-european-union-tnt009-treatment-autoimmune-hemolytic-anemia-including-cold-agglutinin-disease-cad/ (accessed 28.02.16.).
17. [17] Omeros Announces Additional Positive Data in OMS721 Phase 2 Clinical Trial [Press Release] Omeros. 18 2015 http://investor.omeros.com/phoenix.zhtml?c=219263&p=irol-newsArticle_Print&ID=2080177 (accessed 16.02.16.).
18. [18] Boross, P., Yildiz, C., Simons, P.J., Boon, L., Hack, C.E., A monoclonal antibody against complement C2, as a novel complement inhibitor. Altant Conference 2016: Innate Host Defence Utrecht, The Netherlands, 2016.
19. [19] Jore, M.M., Johnson, S., Sheppard, D., Barber, N.M., Li, Y.I., Nunn, M.A., et al. Structural basis for therapeutic inhibition of complement C5. Nat. Struct. Mol. Biol. 23 (2016), 378–386.
20. [20] Rother, R.P., Rollins, S.A., Mojcik, C.F., Brodsky, R.A., Bell, L., Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25 (2007), 1256–1264.
21. [21] Mastellos, D.C., Ricklin, D., Yancopoulou, D., Risitano, A., Lambris, J.D., Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape. Expert Rev. Hematol. 7 (2014), 583–598.
22. [22] Nester, C.M., Barbour, T., de Cordoba, S.R., Dragon-Durey, M.A., Fremeaux-Bacchi, V., Goodship, T.H., et al. Atypical aHUS: State of the art. Mol. Immunol. 67 (2015), 31–42.
23. [23] Coyle, D., Cheung, M.C., Evans, G.A., Opportunity cost of funding drugs for rare diseases: the cost-effectiveness of eculizumab in paroxysmal nocturnal hemoglobinuria. Med. Decis. Making 34 (2014), 1016–1029.
24. [24] Nishimura, J., Yamamoto, M., Hayashi, S., Ohyashiki, K., Ando, K., Brodsky, A.L., et al. Genetic variants in C5 and poor response to eculizumab. New Engl. J. Med. 370 (2014), 632–639.
25. [25] Sahelijo, L., Mujeebuddin, A., Mitchell, D., Larouche, R., Yu, Z.-X., Zhang, Y., et al. First in human single-Ascending dose study: safety, biomarker, pharmacokinetics and exposure-Response relationships of ALXN1210, a humanized monoclonal antibody to C5, with marked half-Life extension and potential for significantly longer dosing intervals. Blood, 126, 2015, 4777.
26. [26] Adis Insight, Drug Profile: ALXN 5500. 2015 (accessed 28.02.16.) http://adisinsight.springer.com/drugs/800042004.
27. [27] InflaRx announces positive phase IIa top-line results from the SCIENS trial investigating IFX-1, a first-in-class anti-complement C5a antibody. [Press Release] InflaRx. 28 2016 http://www.inflarx.de/dam/Inflarx/News/20160128-press-release-IFX-1_PIIa-SCIENS_ENG_final/20160128pressreleaseIFX-1_PIIaSCIENS_ENG_final.pdf (accessed: 28.02.16.).
28. [28] Hoehlig, K., Maasch, C., Shushakova, N., Buchner, K., Huber-Lang, M., Purschke, W.G., et al. A novel C5a-neutralizing mirror-image (l-)aptamer prevents organ failure and improves survival in experimental sepsis. Mol. Ther. 21 (2013), 2236–2246.
29. [29] Woodruff, T.M., Nandakumar, K.S., Tedesco, F., Inhibiting the C5-C5a receptor axis. Mol. Immunol. 48 (2011), 1631–1642.
30. [30] ChemoCentryx Announces Positive Results in Phase II ANCA-Associated Vasculitis CLEAR Trial of Orally Administered Complement 5a Receptor Inhibitor CCX168. [Press Release] ChemoCentryx. 2016 http://ir.chemocentryx.com/releasedetail.cfm?releaseid=948998 (accessed 26.02.16.).
31. [31] Zipfel, P.F., Skerka, C., Chen, Q., Wiech, T., Goodship, T., Johnson, S., et al. The role of complement in C3 glomerulopathy. Mol. Immunol. 67 (2015), 21–30.
32. [32] Ricklin, D., Lambris, J.D., Therapeutic control of complement activation at the level of the central component C3. Immunobiology 221 (2016), 740–746.
33. [33] Ricklin, D., Manipulating the mediator: modulation of the alternative complement pathway C3 convertase in health, disease and therapy. Immunobiology 217 (2012), 1057–1066.
34. [34] Paixao-Cavalcante, D., Torreira, E., Lindorfer, M.A., Rodriguez de Cordoba, S., Morgan, B.P., Taylor, R.P., et al. A humanized antibody that regulates the alternative pathway convertase: potential for therapy of renal disease associated with nephritic factors. J. Immunol. 192 (2014), 4844–4851.
35. [35] Katschke, K.J. Jr., Stawicki, S., Yin, J., Steffek, M., Xi, H., Sturgeon, L., et al. Structural and functional analysis of a C3b-specific antibody that selectively inhibits the alternative pathway of complement. J. Biol. Chem. 284 (2009), 10473–10479.
36. [36] S. Flohr, U. Hommel, E.L.J. Lorthiois, J.K. Maibaum, N. Ostermann, S.A. Randl, et al. Pyrrolidine derivatives and their use as complement pathway modulators Novartis AG. Patent Application: W O20140 02052 (2014).
37. [37] Abdel-Magid, A.F., Factor d inhibitors for the treatment of AMD: patent highlights. ACS Med. Chem. Lett. 3 (2012), 781–782.
38. [38] Gavriilaki, E., Thanassi, J.A., Yang, G., Yuan, X., Huang, M., Brodsky, R.A., Small molecule factor d inhibitors block complement activation in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome [Abstract]. Blood, 126, 2015, 275.
39. [39] Achillion Initiates Phase 1 Study of ACH-4471, First Orally-Administered Small Molecule Complement Factor D Inhibitor [Press Release] 11 2016 http://ir.achillion.com/releasedetail.cfm?ReleaseID=954439 (accessed 28.02.16.).
40. [40] Anderson, K., Liao, S.-M., Maibaum, J., Cumin, F., Delgado, O., Erkenez, A.D., et al. A novel oral small molecule Factor D inhibitor blocks complement activation in the blood and ocular tissues. ARVO Annual Meeting, Seattle WA, 2016.
41. [41] Crowley, M., Delgado, O., Anderson, K., Zheng, W., Sellner, H., Mainol, N., et al. Ocular complement activation and inhibition in rodent models of endotoxin-induced uveitis. ARVO 2016 Annual Meeting, Seattle WA, 2016.
42. [42] Johnson, L., Splawski, I., Baker, L., Carrion, A., Nguyen, A., Twarog, M., et al. Generation and characterization of CLG561: a fully-human. Anti-properdin Fab for the Treatment of Age-related Macular Degeneration ARVO 2016 Annual Meeting, Seattle, WA, 2016.
43. [43] Ricklin, D., Lambris, J.D., Progress and trends in complement therapeutics. Adv. Exp. Med. Biol. 735 (2013), 1–22.
44. [44] Holers, V.M., Rohrer, B., Tomlinson, S., CR2-mediated targeting of complement inhibitors: bench-to-bedside using a novel strategy for site-specific complement modulation. Adv. Exp. Med. Biol. 735 (2013), 137–154.
45. [45] Lachmann, P.J., Lay, E., Seilly, D.J., Buchberger, A., Schwaeble, W., Khadake, J., Further studies of the down-regulation by Factor I of the C3b feedback cycle using endotoxin as a soluble activator and red cells as a source of CR1 on sera of different complotype. Clin. Exp. Immunol. 183 (2016), 150–156.
46. [46] Vogel, C.W., Finnegan, P.W., Fritzinger, D.C., Humanized cobra venom factor: structure, activity, and therapeutic efficacy in preclinical disease models. Mol. Immunol. 61 (2014), 191–203.
47. [47] Mastellos, D.C., Yancopoulou, D., Kokkinos, P., Huber-Lang, M., Hajishengallis, G., Biglarnia, A.R., et al. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur. J. Clin. Invest. 45 (2015), 423–440.
48. [48] Qu, H., Ricklin, D., Bai, H., Chen, H., Reis, E.S., Maciejewski, M., et al. New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology 218 (2013), 496–505.
49. [49] Amyndas’ lead candidate AMY-101 receives orphan drug status from the FDA and the EMA for the treatment of C3 glomerulopathy. [Press Release] Amyndas Pharmaceuticals. 29 2016 http://www.fiercepharma.com/press-releases/amyndas-lead-candidate-amy-101-receives-orphan-drug-status-fda-and-ema-trea (accessed: 2.03.16.).
50. [50] Qu, H., Ricklin, D., Lambris, J.D., Recent developments in low molecular weight complement inhibitors. Mol. Immunol. 47 (2009), 185–195.
51. [51] Melis, J.P., Strumane, K., Ruuls, S.R., Beurskens, F.J., Schuurman, J., Parren, P.W., Complement in therapy and disease: regulating the complement system with antibody-based therapeutics. Mol. Immunol. 67 (2015), 117–130.
52. [52] Katschke, K.J. Jr., Wu, P., Ganesan, R., Kelley, R.F., Mathieu, M.A., Hass, P.E., et al. Inhibiting alternative pathway complement activation by targeting the factor D exosite. J. Biol. Chem. 287 (2012), 12886–12892.
53. [53] Roguska, M., Splawski, I., Diefenbach-Streiber, B., Dolan, E., Etemad-Gilbertson, B., Rondeau, J.-M., et al. Generation and characterization of LFG316, a fully-Human anti-C5 antibody for the treatment of age-Related macular degeneration. Invest. Ophthalmol. Vis. Sci., 55, 2014, 3433.
54. [54] Sobi report for the second quarter 2015 [Press Release] Sobi. 16 July 2015. http://hugin.info/134557/R/1939169/699553.pdf (accessed 28.02.16.).
55. [55] Hepburn, N.J., Williams, A.S., Nunn, M.A., Chamberlain-Banoub, J.C., Hamer, J., Morgan, B.P., et al. In vivo characterization and therapeutic efficacy of a C5-specific inhibitor from the soft tick Ornithodoros moubata. J. Biol. Chem. 282 (2007), 8292–8299.
56. [56] Ra Pharmaceuticals Announces Initiation of First-in-Human Clinical Trial of Novel Complement C5 Inhibitor. [Press Release] Ra Pharmaceuticals. 2 2015 http://www.rapharma.com/global/downloads/Ra-Pharma-PR-120115-Phase-1-ASH-FINAL.pdf (accessed: 2.05.16.).
57. [57] N. Najaan, A. Hill, J. Taubel, J. Bush, A. Borodovsky, N. Kawahata, et al. A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 For Treatment Of PHN And Complement-Mediated Diseases: Interim Phase 1 Study Results 53rd ERA-EDTA Congress. Vienna, Austria (2016).
58. [58] Updated Healthy Volunteer Data from Phase 1/2 Clinical Study with ALN-CC5 for the Treatment of Complement-Mediated Diseases. [Press Release] Alnylam Pharmaceuticals. 22 May 2016. http://www.alnylam.com/capella/presentations/updated-healthy-volunteer-data-from-aln-cc5/ (accessed: 24.05.16.).
59. [59] Grossman, T.R., Hettrick, L.A., Johnson, R.B., Hung, G., Peralta, R., Watt, A., et al. Inhibition of the alternative complement pathway by antisense oligonucleotides targeting complement factor B improves lupus nephritis in mice. Immunobiology, 2015.
60. [60] Grossman, T.R., Antisense Therapies Targeting Complement in Renal Disease. Complement: Driver of Inflammation and Therapeutic Target in Diverse Diseases. 2015, Royal Society, Chicheley Hall, UK.
61. [61] Kolev, M., Le Friec, G., Kemper, C., Complement–tapping into new sites and effector systems. Nat. Rev. Immunol. 14 (2014), 811–820.
62. [62] Zhang, Y., Nester, C.M., Holanda, D.G., Marsh, H.C., Hammond, R.A., Thomas, L.J., et al. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J. Am. Soc. Nephrol. 24 (2013), 1820–1829.
63. [63] Celldex Reports Fiscal 2013 Business/Financial Results and Outlines 2014 Strategy [Press Release] Celldex Therapeutics. 3 March 2014. http://files.shareholder.com/downloads/ABEA-39HH7S/1545539254x0x730319/9BAC77CA-DAAD-4F55-8231-77E4BF9C6140/CLDX_News_2014_3_3_General_Releases.pdf (accessed 16.02.16.).
64. [64] Xiao, F., Ma, L., Zhao, M., Smith, R.A., Huang, G., Jones, P.M., et al. APT070 (mirococept), a membrane-localizing C3 convertase inhibitor, attenuates early human islet allograft damage in vitro and in vivo in a humanized mouse model. Br. J. Pharmacol. 173 (2016), 575–587.
65. [65] Patel, H., Smith, R.A., Sacks, S.H., Zhou, W., 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 (2006), 1102–1111.
66. [66] Hebecker, M., Alba-Dominguez, M., Roumenina, L.T., Reuter, S., Hyvarinen, S., Dragon-Durey, M.A., et al. An engineered construct combining complement regulatory and surface-recognition domains represents a minimal-size functional factor H. J. Immunol. 191 (2013), 912–921.
67. [67] Schmidt, C.Q., Bai, H., Lin, Z., Risitano, A.M., Barlow, P.N., Ricklin, D., et al. Rational engineering of a minimized immune inhibitor with unique triple-targeting properties. J. Immunol. 190 (2013), 5712–5721.
68. [68] Schmidt, C.Q., Harder, M.J., Nichols, E.M., Hebecker, M., Anliker, M., Hochsmann, B., et al. Selectivity of C3-opsonin targeted complement inhibitors: a distinct advantage in the protection of erythrocytes from paroxysmal nocturnal hemoglobinuria patients. Immunobiology 221 (2016), 503–511.
69. [69] Fridkis-Hareli, M., Storek, M., Mazsaroff, I., Risitano, A.M., Lundberg, A.S., Horvath, C.J., et al. Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway-mediated diseases. Blood 118 (2011), 4705–4713.
70. [70] Risitano, A.M., Storek, M., Sahelijo, L., Doyle, M., Dai, Y., Weitz, I.C., et al. Safety and pharmacokinetics of the complement inhibitor tt30 in a phase i trial for untreated pnh patients [abstract]. ASH 57th Annual Meeting & Exposition, Orlando, FL, 2015.
71. [71] Holers, M., Banda, N., Mehta, G., Fridkis-Hareli, M., Or, E., Storek, M., et al. The human complement receptor type 2 (CR2)/CR1 fusion protein TT32, a targeted inhibitor of the classical and alternative pathway C3 convertases, prevents arthritis in active immunization and passive transfer models and acts by CR2-dependent targeting of CR1 regulatory activity. Immunobiology, 217, 2012, 1210.
72. [72] Ruseva, M.M., Ramaglia, V., Morgan, B.P., Harris, C.L., An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), 14319–14324.
73. [73] Nordmaj, M.A., Munthe-Fog, L., Hein, E., Skjoedt, M.O., Garred, P., Genetically engineered fusion of MAP-1 and factor H domains 1–5 generates a potent dual upstream inhibitor of both the lectin and alternative complement pathways. FASEB J. 29 (2015), 4945–4955.
74. [74] Nilsson, P.H., Ekdahl, K.N., Magnusson, P.U., Qu, H., Iwata, H., Ricklin, D., et al. Autoregulation of thromboinflammation on biomaterial surfaces by a multicomponent therapeutic coating. Biomaterials 34 (2013), 985–994.
75. [75] Wu, Y.Q., Qu, H., Sfyroera, G., Tzekou, A., Kay, B.K., Nilsson, B., et al. Protection of nonself surfaces from complement attack by factor H-binding peptides: implications for therapeutic medicine. J. Immunol. 186 (2011), 4269–4277.
76. [76] Lambris, J.D., Ricklin, D., Geisbrecht, B.V., Complement evasion by human pathogens. Nat. Rev. Microbiol. 6 (2008), 132–142.
77. [77] Georgoutsou-Spyridonos, M., Ricklin, D., Pratsinis, H., Perivolioti, E., Pirmettis, I., Garcia, B.L., et al. Attenuation of staphylococcus aureus-Induced bacteremia by human mini-Antibodies targeting the complement inhibitory protein efb. J. Immunol. 195 (2015), 3946–3958.
78. [78] van der Veen, S., Johnson, S., Jongerius, I., Malik, T., Genovese, A., Santini, L., et al. Nonfunctional variant 3 factor H binding proteins as meningococcal vaccine candidates. Infect. Immun. 82 (2014), 1157–1163.
79. [79] de Cordoba, S.R., Tortajada, A., Harris, C.L., Morgan, B.P., Complement dysregulation and disease: from genes and proteins to diagnostics and drugs. Immunobiology 217 (2012), 1034–1046.
80. [80] DeZern, A.E., Uknis, M., Yuan, X., Mukhina, G.L., Varela, J., Saye, J., et al. Complement blockade with a C1 esterase inhibitor in paroxysmal nocturnal hemoglobinuria. Exp. Hematol. 42 (2014), 857–861 e851.
81. [81] Risitano, A.M., Ricklin, D., Huang, Y., Reis, E.S., Chen, H., Ricci, P., et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123 (2014), 2094–2101.
82. [82] Nester, C.M., Brophy, P.D., Eculizumab in the treatment of atypical haemolytic uraemic syndrome and other complement-mediated renal diseases. Curr. Opin. Pediatr. 25 (2013), 225–231.
83. [83] Noris, M., Mescia, F., Remuzzi, G.S.T.E.C.-H.U.S., atypical HUS and TTP are all diseases of complement activation. Nat. Rev. Nephrol. 8 (2012), 622–633.
84. [84] Zhang, Y., Shao, D., Ricklin, D., Hilkin, B.M., Nester, C.M., Lambris, J.D., et al. Compstatin analog Cp40 inhibits complement dysregulation in vitro in C3 glomerulopathy. Immunobiology 220 (2015), 993–998.
85. [85] Mojcik, C.F., Kremer, J., Bingham, C., Burch, F., Vitiello, S., McCroskery, E., et al. Results of a phase 2 B study of the humanized anti-C5 antibody eculizumab in patients with rheumatoid arthritis. Ann. Rheum. Dis., 63, 2004, 301.
86. [86] Vergunst, C.E., Gerlag, D.M., Dinant, H., Schulz, L., Vinkenoog, M., Smeets, T.J., et al. Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation. Rheumatology (Oxford). 46 (2007), 1773–1778.
87. [87] Holers, V.M., Targeting mechanisms at sites of complement activation for imaging and therapy. Immunobiology, 2015.
88. [88] Sacks, S.H., Zhou, W., The role of complement in the early immune response to transplantation. Nat. Rev. Immunol. 12 (2012), 431–442.
89. [89] Fremeaux-Bacchi, V., Legendre, C.M., The emerging role of complement inhibitors in transplantation. Kidney Int. 88 (2015), 967–973.
90. [90] Morgan, B.P., The role of complement in neurological and neuropsychiatric diseases. Expert Rev. Clin. Immunol. 11 (2015), 1109–1119.
91. [91] Chen Song, S., Zhong, S., Xiang, Y., Li, J.H., Guo, H., Wang, W.Y., et al. Complement inhibition enables renal allograft accommodation and long-term engraftment in presensitized nonhuman primates. Am. J. Transplant. 11 (2011), 2057–2066.
92. [92] Biglarnia, A.R., Ekdahl, K.N., Nilsson, B., Complement interception across humoral incompatibility in solid organ transplantation: a clinical perspective. Adv. Exp. Med. Biol. 865 (2015), 211–233.
93. [93] Cooper, D.K., Ekser, B., Tector, A.J., Immunobiological barriers to xenotransplantation. Int. J. Surg. 23 (2015), 211–216.
94. [94] DeAngelis, R.A., Reis, E.S., Ricklin, D., Lambris, J.D., Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis. Immunobiology 217 (2012), 1097–1105.
95. [95] Ekdahl, K.N., Lambris, J.D., Elwing, H., Ricklin, D., Nilsson, P.H., Teramura, Y., et al. Innate immunity activation on biomaterial surfaces: a mechanistic model and coping strategies. Adv. Drug Deliv. Rev. 63 (2011), 1042–1050.
96. [96] Reis, E.S., DeAngelis, R.A., Chen, H., Resuello, R.R., Ricklin, D., Lambris, J.D., Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters. Immunobiology 220 (2015), 476–482.
97. [97] Szebeni, J., Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol. Immunol. 61 (2014), 163–173.
98. [98] Hageman, G.S., Anderson, D.H., Johnson, L.V., Hancox, L.S., Taiber, A.J., Hardisty, L.I., et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. U. S. A. 102 (2005), 7227–7232.
99. [99] van Lookeren Campagne, M., Strauss, E.C., Yaspan, B.L., Age-related macular degeneration: complement in action. Immunobiology, 2015.
100. [100] Regillo C.D., Yaspan BL, Li Z, Dressen A, van Lookeren Campagne M, Graham R, et al. On behalf of the MAHALO Study Investigators. Lampalizumab (Anti-factor D) in Patients with Geographic Atrophy: the MAHALO Phase II Results. 117th Annual AAO meeting, New Orleans, LA.2013.
101. [101] Harris, C.L., Heurich, M., Rodriguez de Cordoba S, Morgan BP. The complotype: dictating risk for inflammation and infection. Trends Immunol. 33 (2012), 513–521.
102. [102] Hovland, A., Jonasson, L., Garred, P., Yndestad, A., Aukrust, P., Lappegard, K.T., et al. The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis. Atherosclerosis 241 (2015), 480–494.
103. [103] Fonseca, M.I., Ager, R.R., Chu, S.H., Yazan, O., Sanderson, S.D., LaFerla, F.M., et al. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J. Immunol. 183 (2009), 1375–1383.
104. [104] Lambert, J.C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41 (2009), 1094–1099.
105. [105] Brennan, F.H., Lee, J.D., Ruitenberg, M.J., Woodruff, T.M., Therapeutic targeting of complement to modify disease course and improve outcomes in neurological conditions. Semin. Immunol., 2016.
106. [106] Barratt-Due, A., Pischke, S.E., Brekke, O.L., Thorgersen, E.B., Nielsen, E.W., Espevik, T., et al. Bride and groom in systemic inflammation–the bells ring for complement and Toll in cooperation. Immunobiology 217 (2012), 1047–1056.
107. [107] Silasi-Mansat, R., Zhu, H., Georgescu, C., Popescu, N., Keshari, R.S., Peer, G., et al. Complement inhibition decreases early fibrogenic events in the lung of septic baboons. J. Cell. Mol. Med., 2015.
108. [108] Silasi-Mansat, R., Zhu, H., Popescu, N.I., Peer, G., Sfyroera, G., Magotti, P., et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116 (2010), 1002–1010.
109. [109] Barratt-Due, A., Thorgersen, E.B., Egge, K., Pischke, S., Sokolov, A., Hellerud, B.C., et al. Combined inhibition of complement C5 and CD14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis. J. Immunol. 191 (2013), 819–827.
110. [110] Huber-Lang, M., Kovtun, A., Ignatius, A., The role of complement in trauma and fracture healing. Semin. Immunol. 25 (2013), 73–78.
111. [111] Rafail, S., Kourtzelis, I., Foukas, P.G., Markiewski, M.M., DeAngelis, R.A., Guariento, M., et al. Complement deficiency promotes cutaneous wound healing in mice. J. Immunol. 194 (2015), 1285–1291.
112. [112] Brennan, F.H., Gordon, R., Lao, H.W., Biggins, P.J., Taylor, S.M., Franklin, R.J., et al. The complement receptor C5aR controls acute inflammation and astrogliosis following spinal cord injury. J. Neurosci. 35 (2015), 6517–6531.
113. [113] Hajishengallis, G., Abe, T., Maekawa, T., Hajishengallis, E., Lambris, J.D., Role of complement in host-microbe homeostasis of the periodontium. Semin. Immunol. 25 (2013), 65–72.
114. [114] Hajishengallis, G., Maekawa, T., Abe, T., Hajishengallis, E., Lambris, J.D., Complement involvement in periodontitis: molecular mechanisms and rational therapeutic approaches. Adv. Exp. Med. Biol. 865 (2015), 57–74.
115. [115] Maekawa, T., Abe, T., Hajishengallis, E., Hosur, K.B., DeAngelis, R.A., Ricklin, D., et al. Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. J. Immunol. 192 (2014), 6020–6027.
116. [116] Abe, T., Hosur, K.B., Hajishengallis, E., Reis, E.S., Ricklin, D., Lambris, J.D., et al. Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. J. Immunol. 189 (2012), 5442–5448.
117. [117] Maekawa, T., Briones, R.A., Resuello, R.R., Tuplano, J.V., Hajishengallis, E., Kajikawa, T., et al. Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. J. Clin. Periodontol., 2016.
118. [118] Chehoud, C., Rafail, S., Tyldsley, A.S., Seykora, J.T., Lambris, J.D., Grice, E.A., Complement modulates the cutaneous microbiome and inflammatory milieu. Proc. Natl. Acad. Sci. U. S. A. 110 (2013), 15061–15066.
119. [119] Taylor, R.P., Lindorfer, M.A., The role of complement in mAb-based therapies of cancer. Methods 65 (2014), 18–27.
120. [120] Mamidi, S., Hone, S., Kirschfink, M., The complement system in cancer: ambivalence between tumour destruction and promotion. Immunobiology, 2015.
121. [121] Pio, R., Ajona, D., Lambris, J.D., Complement inhibition in cancer therapy. Semin. Immunol. 25 (2013), 54–64.
122. [122] Markiewski, M.M., DeAngelis, R.A., Benencia, F., Ricklin-Lichtsteiner, S.K., Koutoulaki, A., Gerard, C., et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 9 (2008), 1225–1235.
123. [123] Vadrevu, S.K., Chintala, N.K., Sharma, S.K., Sharma, P., Cleveland, C., Riediger, L., et al. Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche. Cancer Res. 74 (2014), 3454–3465.
124. [124] SR, E., Falcao, D.A., Issac, L., 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 (2006), 155–168.
125. [125] Cagliani, R., Forni, D., Filippi, G., Mozzi, A., De Gioia, L., Pontremoli, C., et al. The mammalian complement system as an epitome of host-pathogen genetic conflicts. Mol. Ecol., 2016.
126. [126] Berends, E.T., Mohan, S., Miellet, W.R., Ruyken, M., Rooijakkers, S.H., Contribution of the complement Membrane Attack Complex to the bactericidal activity of human serum. Mol. Immunol. 65 (2015), 328–335.
127. [127] Macedo, A.C., Isaac, L., Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway. Front. Immunol., 7, 2016, 55.
128. [128] Scott, D., Botto, M., The paradoxical roles of C1q and C3 in autoimmunity. Immunobiology, 2015.
129. [129] Wu, M.A., Zanichelli, A., Mansi, M., Cicardi, M., Current treatment options for hereditary angioedema due to C1 inhibitor deficiency. Expert Opin. Pharmacother. 17 (2016), 27–40.
130. [130] Risitano, A.M., Paroxysmal Nocturnal Hemoglobinuria in the era of complement inhibition. Am. J. Hematol., 2016.
131. [131] Loschi, M., Porcher, R., Barraco, F., Terriou, L., Mohty, M., de Guibert, S., et al. Impact of eculizumab treatment on paroxysmal nocturnal hemoglobinuria: a treatment versus no-treatment study. Am. J. Hematol., 2015.
132. [132] Hillmen, P., Muus, P., Szer, J., Hill, A., Hochsmann, B., Kulasekararaj, A., et al. Assessment of human antihuman antibodies to eculizumab after long-term treatment in patients with paroxysmal nocturnal hemoglobinuria. Am. J. Hematol. 91 (2016), E16–17.
133. [133] Hillmen, P., Muus, P., Roth, A., Elebute, M.O., Risitano, A.M., Schrezenmeier, H., et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 162 (2013), 62–73.
134. [134] Wang, J., Wang, L., Xiang, Y., Ricklin, D., Lambris, J.D., Chen, G., Using an in vitro xenoantibody-mediated complement-dependent cytotoxicity model to evaluate the complement inhibitory activity of the peptidic C3 inhibitor Cp40. Clin. Immunol. 162 (2016), 37–44.
135. [135] Hamad, O.A., Mitroulis, I., Fromell, K., Kozarcanin, H., Chavakis, T., Ricklin, D., et al. Contact activation of C3 enables tethering between activated platelets and polymorphonuclear leukocytes via CD11b/CD18. Thromb. Haemost. 114 (2015), 1207–1217.
136. [136] Loyet, K.M., Good, J., Davancaze, T., Sturgeon, L., Wang, X., Yang, J., et al. Complement inhibition in cynomolgus monkeys by anti-factor d antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration. J. Pharmacol. Exp. Ther. 351 (2014), 527–537.
137. [137] Marsh, J.E., Zhou, W., Sacks, S.H., Local tissue complement synthesis–fine tuning a blunt instrument. Arch. Immunol. Ther. Exp. (Warsz) 49:Suppl. 1 (2001), S41–46.
138. [138] Huang, Y., Reis, E.S., Knerr, P.J., van der Donk, W.A., Ricklin, D., Lambris, J.D., Conjugation to albumin-binding molecule tags as a strategy to improve both efficacy and pharmacokinetic properties of the complement inhibitor compstatin. ChemMedChem 9 (2014), 2223–2226.