Clinical promise of next-generation complement therapeutics

Nature Reviews Drug Discovery

Volumn 18, Issue 9, 2019, Pages 707-729

  Mastellos, Dimitrios C ^a   Ricklin, Daniel ^b   Lambris, John D ^c  

^a INSTITUTE OF NANOSCIENCE AND NANOTECHNOLOGY   (Greece)

^b UNIVERSITY OF BASEL   (Switzerland)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (DODECYLDIMETHYLAMMONIO) 1 PROPANESULFONIC ACID; ABP 959; ALX 1210; AVACINCAPTAD PEGOL; AVACOPAN; BIOLOGICAL MARKER; BIV 009; CDX 1135; CEMDISIRAN; CETOR; CLG 561; COMPLEMENT COMPONENT C1S INHIBITOR; COMPLEMENT INHIBITOR; CROVALIMAB; DANICOPAN; DEXTRO TYROSYLISOLEUCYLCYSTEINYLVALYL 1 METHYLTRYPTOPHYLGLUTAMINYLASPARTYLTRYPTOPHYL N METHYLGLYCYLALANYLHISTIDYLARGINYLCYSTEINYL N METHYLISOLEUCINAMIDE 3,13 CYCLIC SULFIDE; ECULIZUMAB; GEN 1029; IFX 1; IPH 5401; LAMPALIZUMAB; LFG 316; LNP 023; LPN 023; MIROCOCEPT; NARSOPLIMAB; NOMACOPAN; PEGCETACOPLAN; POZELIMAB; RAVULIZUMAB; SUTIMLIMAB; TESIDOLUMAB; UNCLASSIFIED DRUG; ZILUCOPLAN; COMPLEMENT;

ANCA ASSOCIATED VASCULITIS; ANTIBODY MEDIATED REJECTION; AUTOIMMUNE DISEASE; AUTOIMMUNE HEMOLYTIC ANEMIA; BLOOD GROUP ABO INCOMPATIBILITY; CHRONIC KIDNEY FAILURE; CLINICAL RESEARCH; COMPLEMENT SYSTEM; DRUG COST; DRUG DEVELOPMENT; DRUG INDICATION; DRUG SAFETY; DRUG TARGETING; EYE DISEASE; GLOMERULOPATHY; HEART INFARCTION; HEMATOLOGIC DISEASE; HEMODIALYSIS; HEMOLYTIC UREMIC SYNDROME; HUMAN; IMMUNE RESPONSE; IMMUNOGLOBULIN A NEPHROPATHY; INFLAMMATION; INJURY; KIDNEY GRAFT REJECTION; KIDNEY TRANSPLANTATION; MALIGNANT NEOPLASM; MULTIPLE ORGAN FAILURE; MYELOOPTIC NEUROPATHY; NEUROMUSCULAR DISEASE; NONHUMAN; ORGAN TRANSPLANTATION; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PERIODONTAL DISEASE; PERSONALIZED MEDICINE; PRIORITY JOURNAL; RECURRENT DISEASE; RENAL ISCHEMIA REPERFUSION INJURY; REVIEW; SEPSIS; SUPPURATIVE HIDRADENITIS; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME; THROMBOTIC THROMBOCYTOPENIC PURPURA; BIOLOGICAL MODEL; CHRONIC DISEASE; COMPLEMENT ACTIVATION; DRUG EFFECT; IMMUNOLOGY; PROCEDURES;

CHRONIC DISEASE; COMPLEMENT ACTIVATION; COMPLEMENT INACTIVATING AGENTS; COMPLEMENT SYSTEM PROTEINS; DRUG DISCOVERY; HUMANS; INFLAMMATION; MODELS, BIOLOGICAL;

EID: 85069495618     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/s41573-019-0031-6     Document Type: Review

References (257)

1. Ricklin, D., Reis, E. S. & Lambris, J. D. Complement in disease: a defence system turning offensive. Nat. Rev. Nephrol. 12, 383–401 (2016).
2. Rankin, L. C. & Artis, D. Beyond host defense: emerging functions of the immune system in regulating complex tissue physiology. Cell 173, 554–567 (2018).
3. Ricklin, D., Hajishengallis, G., Yang, K. & Lambris, J. D. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11, 785–797 (2010). This article provides an introductory overview of the mechanisms and functions of complement in tissue homeostasis and host immunosurveillance.
4. Hajishengallis, G., Reis, E. S., Mastellos, D. C., Ricklin, D. & Lambris, J. D. Novel mechanisms and functions of complement. Nat. Immunol. 18, 1288–1298 (2017).
5. Ricklin, D. & Lambris, J. D. Preformed mediators of defense — gatekeepers enter the spotlight. Immunol. Rev. 274, 5–8 (2016).
6. 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, 262 (2015).
7. Forneris, F. et al. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 330, 1816–1820 (2010).
8. Carroll, M. C. & Isenman, D. E. Regulation of humoral immunity by complement. Immunity 37, 199–207 (2012).
9. Reis, E. S., Mastellos, D. C., Hajishengallis, G. & Lambris, J. D. New insights into the immune functions of complement. Nat. Rev. Immunol. 10.1038/s41577-019-0168-x (2019). This review discusses new insights on how complement-triggered pathways shape innate and adaptive immune responses in convergence with other pattern recognition systems.
10. Ekdahl, K. N., Soveri, I., Hilborn, J., Fellstrom, B. & Nilsson, B. Cardiovascular disease in haemodialysis: role of the intravascular innate immune system. Nat. Rev. Nephrol. 13, 285–296 (2017).
11. Ricklin, D. & Lambris, J. D. Complement in immune and inflammatory disorders: therapeutic interventions. J. Immunol. 190, 3839–3847 (2013).
12. Schmidt, C. Q., Lambris, J. D. & Ricklin, D. Protection of host cells by complement regulators. Immunol. Rev. 274, 152–171 (2016).
13. Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012). This article provides a comprehensive review of the multifaceted role of complement in shaping central nervous system development and synaptic networks in both health and disease.
14. Hajishengallis, G. et al. Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application. Semin. Immunol. 28, 285–291 (2016).
15. van Lookeren, C. M., Strauss, E. C. & Yaspan, B. L. Age-related macular degeneration: complement in action. Immunobiology 221, 733–739 (2016).
16. Morgan, B. P. & Harris, C. L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 14, 857–877 (2015).
17. Ricklin, D. & Lambris, J. D. Complement therapeutics. Semin. Immunol. 28, 205–207 (2016).
18. Ricklin, D., Mastellos, D. C., Reis, E. S. & Lambris, J. D. The renaissance of complement therapeutics. Nat. Rev. Nephrol. 14, 26–47 (2018).
19. Mastellos, D. C. et al. From orphan drugs to adopted therapies: advancing C3-targeted intervention to the clinical stage. Immunobiology 221, 1046–1057 (2016).
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, 1256–1264 (2007).
21. Frei, Y., Lambris, J. D. & Stockinger, B. Generation of a monoclonal antibody to mouse C5 application in an ELISA assay for detection of anti-C5 antibodies. Mol. Cell. Probes 1, 141–149 (1987). This article describes the generation and characterization of the first mouse anti-C5 monoclonal antibodies that formed the basis for the clinical development and subsequent approval of the anti-C5 mAb, eculizumab.
22. Wang, Y., Rollins, S. A., Madri, J. A. & Matis, L. A. Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease. Proc. Natl Acad. Sci. USA 92, 8955–8959 (1995).
23. Zuber, J., Fakhouri, F., Roumenina, L. T., Loirat, C. & Fremeaux-Bacchi, V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat. Rev. Nephrol. 8, 643–657 (2012).
24. Howard, J. F. et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 16, 976–986 (2017).
25. Varga, L. & Farkas, H. rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency. Expert Rev. Clin. Immunol. 7, 143–153 (2011).
26. Gros, P., Milder, F. J. & Janssen, B. J. Complement driven by conformational changes. Nat. Rev. Immunol. 8, 48–58 (2008).
27. Holz, F. G. et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials. JAMA Ophthalmol. 136, 666–677 (2018). This article presents the results from the two multicentre phase III trials that evaluated the efficacy of the FD-targeting antibody lampalizumab in GA patients.
28. US Food & Drug Administration. FDA approves ravulizumab-cwvz for paroxysmal nocturnal hemoglobinuria. FDA.gov https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ravulizumab-cwvz-paroxysmal-nocturnal-hemoglobinuria (2018).
29. Lee, J. W. et al. Ravulizumab (ALXN1210) versus eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood 133, 530–539 (2018).
30. Kulasekararaj, A. G. et al. Ravulizumab (ALXN1210) versus eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood 133, 540–549 (2018). This clinical study showed that patients with PNH can effectively switch from eculizumab-based therapy to a more patient-compliant, long-acting version of this anti-C5 therapeutic, ravulizumab.
31. Ricklin, D. & Lambris, J. D. New milestones ahead in complement-targeted therapy. Semin. Immunol. 28, 208–222 (2016).
32. Sacks, S. H. & Zhou, W. The role of complement in the early immune response to transplantation. Nat. Rev. Immunol. 12, 431–442 (2012).
33. Mastellos, D. C. et al. Taming hemodialysis-induced inflammation: are complement C3 inhibitors a viable option? Clin. Immunol. 198, 102–105 (2019).
34. Jager, N. M., Poppelaars, F., Daha, M. R. & Seelen, M. A. Complement in renal transplantation: the road to translation. Mol. Immunol. 89, 22–35 (2017).
35. Farrar, C. A. et al. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J. Clin. Invest. 126, 1911–1925 (2016).
36. Nauser, C. L., Howard, M. C., Fanelli, G., Farrar, C. A. & Sacks, S. Collectin-11 (CL-11) is a major sentinel at epithelial surfaces and key pattern recognition molecule in complement-mediated ischaemic injury. Front. Immunol. 9, 2023 (2018).
37. Elvington, A. et al. The alternative complement pathway propagates inflammation and injury in murine ischemic stroke. J. Immunol. 189, 4640–4647 (2012).
38. Dobó, J. et al. MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked. Sci. Rep. 6, 31877 (2016). This article describes a fundamental mechanism by which the AP and LP of complement converge and signifies the importance of ‘bypass’ complement activation modes in health and disease.
39. Chan, R. K. et al. IgM binding to injured tissue precedes complement activation during skeletal muscle ischemia-reperfusion. J. Surg. Res. 122, 29–35 (2004).
40. Castellano, G. et al. Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage. Am. J. Pathol. 176, 1648–1659 (2010).
41. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02134314 (2018).
42. Lazar, H. L. et al. Soluble human complement receptor 1 limits ischemic damage in cardiac surgery patients at high risk requiring cardiopulmonary bypass. Circulation 110, II274–II279 (2004).
43. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00082121 (2007).
44. Li, J. S., Jaggers, J. & Anderson, P. A. The use of TP10, soluble complement receptor 1, in cardiopulmonary bypass. Expert Rev. Cardiovasc. Ther. 4, 649–654 (2006).
45. Lazar, H. L. et al. Beneficial effects of complement inhibition with soluble complement receptor 1 (TP10) during cardiac surgery: is there a gender difference? Circulation 116, I83–I88 (2007).
46. Dodd, I. et al. Overexpression in Escherichia coli, folding, purification, and characterization of the first three short consensus repeat modules of human complement receptor type 1. Protein Expr. Purif. 6, 727–736 (1995).
47. Kassimatis, T. et al. A double-blind randomised controlled investigation into the efficacy of mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial. Trials 18, 255 (2017).
48. Alawieh, A. & Tomlinson, S. Injury site-specific targeting of complement inhibitors for treating stroke. Immunol. Rev. 274, 270–280 (2016).
49. 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, 137–154 (2013).
50. Alawieh, A. et al. Modulation of post-stroke degenerative and regenerative processes and subacute protection by site-targeted inhibition of the alternative pathway of complement. J. Neuroinflamm. 12, 247 (2015).
51. Crunkhorn, S. Stroke: opening the therapeutic window. Nat. Rev. Drug Discov. 17, 467 (2018).
52. Alawieh, A., Langley, E. F. & Tomlinson, S. Targeted complement inhibition salvages stressed neurons and inhibits neuroinflammation after stroke in mice. Sci. Transl Med. 10, eaao6459 (2018). This study underscores the translational potential of targeted complement inhibition in ischaemic stroke.
53. Orsini, F. et al. Mannan binding lectin-associated serine protease-2 (MASP-2) critically contributes to post-ischemic brain injury independent of MASP-1. J. Neuroinflamm. 13, 213 (2016).
54. Omeros Corporation. FDA grants breakthrough therapy designation to Omeros’ MASP-2 inhibitor OMS721 for the treatment of IgA nephropathy. Business Wire https://www.businesswire.com/news/home/20170613005978/en/FDA-Grants-Breakthrough-Therapy-Designation-Omeros’-MASP-2 (2019).
55. Loupy, A. & Lefaucheur, C. Antibody-mediated rejection of solid-organ allografts. N. Engl. J. Med. 379, 1150–1160 (2018).
56. Biglarnia, A.-R., Huber-Lang, M., Mohlin, C., Ekdahl, K. N. & Nilsson, B. The multifaceted role of complement in kidney transplantation. Nat. Rev. Nephrol. 14, 767–781 (2018).
57. Stegall, M. D., Chedid, M. F. & Cornell, L. D. The role of complement in antibody-mediated rejection in kidney transplantation. Nat. Rev. Nephrol. 8, 670–678 (2012).
58. Montgomery, R. A., Tatapudi, V. S., Leffell, M. S. & Zachary, A. A. HLA in transplantation. Nat. Rev. Nephrol. 14, 558–570 (2018).
59. Tatapudi, V. S. & Montgomery, R. A. Pharmacologic complement inhibition in clinical transplantation. Curr. Transplant. Rep. 4, 91–100 (2017).
60. Lefaucheur, C. et al. Complement-activating anti-HLA antibodies in kidney transplantation: allograft gene expression profiling and response to treatment. J. Am. Soc. Nephrol. 29, 620–635 (2018).
61. Stegall, M. D. et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am. J. Transplant. 11, 2405–2413 (2011).
62. Montgomery, R. A. et al. Plasma-derived C1 esterase inhibitor for acute antibody-mediated rejection following kidney transplantation: results of a randomized double-blind placebo-controlled pilot study. Am. J. Transplant. 16, 3468–3478 (2016).
63. Viglietti, D. et al. C1 inhibitor in acute antibody-mediated rejection nonresponsive to conventional therapy in kidney transplant recipients: a pilot study. Am. J. Transplant. 16, 1596–1603 (2016).
64. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02547220 (2019).
65. Ricklin, D. & Lambris, J. D. Therapeutic control of complement activation at the level of the central component C3. Immunobiology 221, 740–746 (2016).
66. Amyndas Pharmaceuticals. Our focus. Amyndas Pharmaceuticals http://amyndas.com/research-focus/ (2019).
67. Bosmann, M. & Ward, P. A. The inflammatory response in sepsis. Trends Immunol. 34, 129–136 (2013).
68. Halbgebauer, R., Schmidt, C. Q., Karsten, C. M., Ignatius, A. & Huber-Lang, M. Janus face of complement-driven neutrophil activation during sepsis. Semin. Immunol. 37, 12–20 (2018).
69. van Griensven, M. et al. Protective effects of the complement inhibitor compstatin Cp40 in hemorrhagic shock. J. Immunol. 51, 78–87 (2018).
70. Silasi-Mansat, R. et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 116, 1002–1010 (2010).
71. Brekke, O. L. et al. The effects of selective complement and CD14 inhibition on the E. coli-induced tissue factor mRNA upregulation, monocyte tissue factor expression, and tissue factor functional activity in human whole blood. Adv. Exp. Med. Biol. 735, 123–136 (2013).
72. Huber-Lang, M. et al. Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. J. Immunol. 192, 5324–5331 (2014).
73. Keshari, R. S. et al. Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of Escherichia coli sepsis. Proc. Natl Acad. Sci. USA 114, E6390–E6399 (2017).
74. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02246595 (2016).
75. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03487276 (2018).
76. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01766414 (2014).
77. Aridis Pharmaceuticals. AR-101 (AerumabTM): fully human mAb against Pseudomonas aeruginosa LPS serotype O11. Aridis Pharmaceuticals https://aridispharma.com/ar-101/ (2019).
78. Poppelaars, F. et al. The complement system in dialysis: a forgotten story? Front. Immunol. 9, 71 (2018).
79. 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, 1097–1105 (2012).
80. Santoro, D. et al. Pain in end-stage renal disease: a frequent and neglected clinical problem. Clin. Nephrol. 79 (Suppl. 1), 2–11 (2013).
81. Poppelaars, F. et al. Intradialytic complement activation precedes the development of cardiovascular events in hemodialysis patients. Front. Immunol. 9, 2070 (2018). This study links HD-induced complement activation with an increased risk of cardiovascular events in HD patients.
82. Reis, E. S. et al. Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters. Immunobiology 220, 476–482 (2015).
83. Craik, D. J., Fairlie, D. P., Liras, S. & Price, D. The future of peptide-based drugs. Chem. Biol. Drug Des. 81, 136–147 (2013).
84. Bray, B. L. Large-scale manufacture of peptide therapeutics by chemical synthesis. Nat. Rev. Drug Discov. 2, 587–593 (2003). This article points to the potential for more affordable biological therapies exploiting the large-scale chemical synthesis of therapeutic peptides.
85. Lamont, R. J., Koo, H. & Hajishengallis, G. The oral microbiota: dynamic communities and host interactions. Nat. Rev. Microbiol. 16, 745–759 (2018).
86. Eke, P. I., Dye, B. A., Wei, L., Thornton-Evans, G. O. & Genco, R. J. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J. Dent. Res. 91, 914–920 (2012).
87. Hajishengallis, G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat. Rev. Immunol. 15, 30–44 (2015).
88. Hajishengallis, G. & Lambris, J. D. Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol. 31, 154–163 (2010).
89. Maekawa, 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. 43, 238–249 (2016).
90. Kajikawa, T. et al. Safety and efficacy of the complement inhibitor AMY-101 in a natural model of periodontitis in non-human primates. Mol. Ther. Methods Clin. Dev. 6, 207–215 (2017).
91. 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, 583–598 (2014).
92. Risitano, A. M. & Marotta, S. Toward complement inhibition 2.0: next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria. Am. J. Hematol. 93, 564–577 (2018).
93. Nishimura, J. et al. Genetic variants in C5 and poor response to eculizumab. N. Engl. J. Med. 370, 632–639 (2014).
94. Armstrong, M. Samsung joins Soliris biosimilar quest. Evaluate http://www.evaluate.com/vantage/articles/news/snippets/samsung-joins-soliris-biosimilar-quest (2019).
95. Mastellos, D. C., Reis, E. S., Yancopoulou, D., Risitano, A. M. & Lambris, J. D. Expanding complement therapeutics for the treatment of paroxysmal nocturnal hemoglobinuria. Semin. Hematol. 55, 167–175 (2018).
96. Reis, E. S., Mastellos, D. C., Ricklin, D., Mantovani, A. & Lambris, J. D. Complement in cancer: untangling an intricate relationship. Nat. Rev. Immunol. 18, 5–18 (2018).
97. Morgan, B. P. The role of complement in neurological and neuropsychiatric diseases. Expert Rev. Clin. Immunol. 11, 1109–1119 (2015).
98. Smith, R. J. H. et al. C3 glomerulopathy — understanding a rare complement-driven renal disease. Nat. Rev. Nephrol. 15, 129–143 (2019). A comprehensive review discussing pathophysiological aspects, patient stratification criteria and therapeutic options for the complement-mediated renal disorder C3G.
99. Jodele, S. Complement in pathophysiology and treatment of transplant-associated thrombotic microangiopathies. Semin. Hematol. 55, 159–166 (2018).
100. Hillmen, P. et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355, 1233–1243 (2006).
101. Hillmen, P. et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 162, 62–73 (2013).
102. Risitano, A. M. et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 113, 4094–4100 (2009).
103. Harder, M. J. et al. Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood 129, 970–980 (2017).
104. Elgin, B., Bloomfield, D. & Chen, C. When the patient is a gold mine: the trouble with rare-disease drugs. Bloomberg https://www.bloomberg.com/news/features/2017-05-24/when-the-patient-is-a-gold-mine-the-trouble-with-rare-disease-drugs (2019). This is a popular article highlighting the significant economic burden associated with the currently approved complement-based therapy in the clinic.
105. America’s Health Insurance Plans. High-priced drugs: estimates of annual per-patient expenditures for 150 specialty medications. AHIP https://www.ahip.org/report-high-priced-drugs-expenditures/ (2016).
106. Sheridan, D. et al. Design and preclinical characterization of ALXN1210: a next generation anti-C5 monoclonal antibody with improved pharmacokinetics and duration of action. Immunobiology 221, 1158 (2016).
107. Röth, A. et al. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv. 2, 2176–2185 (2018).
108. Fukuzawa, T. et al. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci. Rep. 7, 1080 (2017).
109. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02534909 (2019).
110. Adis Insight. Pozelimab — Regeneron Pharmaceuticals. Adis Insight http://adisinsight.springer.com/drugs/800049599 (2018).
111. Hill, A., Weston-Davies, W. H., Nunn, M., Robak, T. & Windyga, J. Coversin, a novel C5 complement inhibitor, is safe and effective in the treatment of PNH: results of a phase II clinical trial. Blood 130, 4747 (2017).
112. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03427060 (2018).
113. Morrison, C. Constrained peptides’ time to shine? Nat. Rev. Drug Discov. 17, 531–533 (2018).
114. Ricardo, A. et al. Preclinical evaluation of RA101495, a potent cyclic peptide inhibitor of C5 for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 126, 939 (2015).
115. Johnston, J. M. et al. Phase 1 multiple-dose clinical study of RA101495, a subcutaneously administered synthetic macrocyclic peptide inhibitor of complement C5 for treatment of paroxysmal nocturnal hemoglobinuria [abstract LB2249]. Haematologica 101 (Suppl. 1), 415 (2016).
116. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03078582 (2018).
117. Hill, A. et al. A subcutaneously administered investigational RNAi therapeutic (ALN-CC5) targeting complement C5 for treatment of PNH and complement-mediated diseases: preliminary phase 1/2 study results in patients with PNH. Blood 128, 3891 (2016).
118. Mastellos, D. C. et al. Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention. Eur. J. Clin. Invest. 45, 423–440 (2015).
119. Ricklin, D. & Lambris, J. D. Compstatin: a complement inhibitor on its way to clinical application. Adv. Exp. Med. Biol. 632, 273–292 (2008).
120. Janssen, B. J., Halff, E. F., Lambris, J. D. & Gros, P. Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition. J. Biol. Chem. 282, 29241–29247 (2007).
121. Risitano, A. M. et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123, 2094–2101 (2014). This is the first study demonstrating proof of efficacy and translational potential for the C3 inhibitory peptides, termed compstatins, in treating PNH.
122. Apellis Pharmaceuticals. Our focus. Apellis Pharmaceuticals http://apellis.com/focus-science.html (2019).
123. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02264639 (2018).
124. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02588833 (2019).
125. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03500549 (2019).
126. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03531255 (2018).
127. Amyndas Pharmaceuticals. Clinical trials. Amyndas Pharmaceuticals http://amyndas.com/clinical-trials/ (2019).
128. Berger, N. et al. New analogs of the complement C3 inhibitor compstatin with increased solubility and improved pharmacokinetic profile. J. Med. Chem. 61, 6153–6162 (2018).
129. Harris, C. L., Pouw, R. B., Kavanagh, D., Sun, R. & Ricklin, D. Developments in anti-complement therapy; from disease to clinical trial. Mol. Immunol. 102, 89–119 (2018). This review discusses the pathophysiological basis of complement-mediated diseases, presenting a detailed description of ongoing clinical trials in various indications.
130. Schubart, A. et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc. Natl Acad. Sci. USA 116, 7926–7931 (2019). This study describes the rational design and preclinical evaluation of an orally available FB inhibitor with clinical potential for the treatment of PNH and other AP-mediated complement disorders.
131. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03439839 (2019).
132. Yuan, X. et al. Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica 102, 466–475 (2017). This study indicates the efficacy and clinical potential of orally available FD inhibitors for the treatment of PNH and other AP-mediated complement disorders.
133. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03053102 (2018).
134. Achillion Pharmaceuticals. Achillion reports positive interim data for ACH-4471 phase 2 trials and provides clinical development strategy update. GlobeNewswire https://globenewswire.com/news-release/2018/12/17/1668298/0/en/Achillion-Reports-Positive-Interim-Data-for-ACH-4471-Phase-2-Trials-and-Provides-Clinical-Development-Strategy-Update.html (2019).
135. Lambris, J. D., Qu, H. & Ricklin, D. Compstatin analogs with improved pharmacokinetic properties. US Patent 9630992B2 (2019).
136. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03347422 (2019).
137. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03347396 (2019).
138. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03226678 (2019).
139. Wang, R. H., Phillips, G., Medof, M. E. & Mold, C. Activation of the alternative complement pathway by exposure of phosphatidylethanolamine and phosphatidylserine on erythrocytes from sickle cell disease patients. J. Clin. Invest. 92, 1326–1335 (1993).
140. Merle, N. S. et al. Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles. JCI Insight 3, 96910 (2018). This study revealed the complement-activating properties of cell-free haem and points to a new mechanism that amplifies complement-mediated injury during intravascular haemolysis.
141. Chonat, S. et al. Contribution of alternative complement pathway to delayed hemolytic transfusion reaction in sickle cell disease. Haematologica 103, e483–e485 (2018).
142. Lombardi, E. et al. Factor H interfers with the adhesion of sickle red cells to vascular endothelium: a novel disease modulating molecule. Haematologica 104, 919–928 (2019).
143. Biryukov, S. & Stoute, J. A. Complement activation in malaria: friend or foe? Trends Mol. Med. 20, 293–301 (2014).
144. Lindorfer, M. A. et al. Compstatin Cp40 blocks hematin-mediated deposition of C3b fragments on erythrocytes: implications for treatment of malarial anemia. Clin. Immunol. 171, 32–35 (2016).
145. Merle, N. S. et al. P-selectin drives complement attack on endothelium during intravascular hemolysis in TLR-4/heme-dependent manner. Proc. Natl Acad. Sci. USA 116, 6280–6285 (2019). This study illustrates the therapeutic potential of targeting P-selectin on endothelial surfaces as a means of blocking complement deposition and attenuating tissue injury in various haemolytic disorders.
146. Jourde-Chiche, N. et al. Endothelium structure and function in kidney health and disease. Nat. Rev. Nephrol. 15, 87–108 (2019).
147. Xiao, X., Pickering, M. C. & Smith, R. J. C3 glomerulopathy: the genetic and clinical findings in dense deposit disease and C3 glomerulonephritis. Semin. Thromb. Hemost. 40, 465–471 (2014).
148. Durey, M. A., Sinha, A., Togarsimalemath, S. K. & Bagga, A. Anti-complement-factor H-associated glomerulopathies. Nat. Rev. Nephrol. 12, 563–578 (2016).
149. Sethi, S. & Fervenza, F. C. Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS). Semin. Thromb. Hemost. 40, 416–421 (2014).
150. Bu, F. et al. Genetic analysis of 400 patients refines understanding and implicates a new gene in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 29, 2809–2819 (2018).
151. Frimat, M. et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 122, 282–292 (2013).
152. Huerta, A. et al. A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome. Kidney Int. 93, 450–459 (2018).
153. Legendre, C. M. et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 368, 2169–2181 (2013).
154. Rathbone, J. et al. A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open 3, e003573 (2013).
155. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03131219 (2018).
156. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02949128 (2019).
157. Alexion Pharmaceuticals. Alexion announces positive top-line results from phase 3 study of ULTOMIRIS™ (Ravulizumab-Cwvz) in complement inhibitor-naïve patients with atypical hemolytic uremic syndrome (aHUS). Alexion Newsroom https://news.alexion.com/press-release/product-news/alexion-announces-positive-top-line-results-phase-3-study-ultomiris-ravul (2019).
158. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02464891 (2017).
159. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03205995 (2018).
160. Vaught, A. J. et al. Germline mutations in the alternative pathway of complement predispose to HELLP syndrome. JCI Insight 3, 99128 (2018).
161. Qi, J. et al. Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation. Ann. Hematol. 96, 1849–1855 (2017).
162. Rotz, S. J. et al. In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy. Blood Adv. 1, 1632–1634 (2017).
163. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03518203 (2019).
164. Goodship, T. H. J. et al. Use of the complement inhibitor Coversin to treat HSCT-associated TMA. Blood Adv. 1, 1254–1258 (2017).
165. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02222545 (2019).
166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02355782 (2015).
167. Pickering, M. C. et al. C3 glomerulopathy: consensus report. Kidney Int. 84, 1079–1089 (2013).
168. Sethi, S. et al. C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int. 82, 465–473 (2012).
169. Servais, A. et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 82, 454–464 (2012).
170. Gale, D. P. et al. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376, 794–801 (2010).
171. Bu, F. et al. High-throughput genetic testing for thrombotic microangiopathies and C3 glomerulopathies. J. Am. Soc. Nephrol. 27, 1245–1253 (2016).
172. Nester, C. M. & Smith, R. J. Complement inhibition in C3 glomerulopathy. Semin. Immunol. 28, 241–249 (2016).
173. Bomback, A. S. et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin. J. Am. Soc. Nephrol. 7, 748–756 (2012).
174. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03301467 (2018).
175. Jayne, D. R. W. et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J. Am. Soc. Nephrol. 28, 2756–2767 (2017).
176. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01363388 (2013).
177. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02682407 (2018).
178. Achillion Pharmaceuticals. Advancing factor D inhibition into late-stage clinical development. Achillion Pharmaceuticals http://www.achillion.com/pipeline/ (2019).
179. Mastellos, D. C., Reis, E. S., Ricklin, D., Smith, R. J. & Lambris, J. D. Complement C3-targeted therapy: replacing long-held assertions with evidence-based discovery. Trends Immunol. 38, 383–394 (2017).
180. Apellis Pharmaceuticals. Apellis Pharmaceuticals’ APL-2 receives orphan drug designation from the FDA for the treatment of C3 glomerulopathy. Apellis Pharmaceuticals http://investors.apellis.com/news-releases/news-release-details/apellis-pharmaceuticals-apl-2-receives-orphan-drug-designation (2019).
181. Amyndas Pharmaceuticals. Press release: Amyndas’ lead candidate AMY-101 receives orphan drug status from the FDA and the EMA for the treatment of C3 glomerulopathy. Amyndas Pharmaceuticals http://amyndas.com/press-release-amyndas-lead-candidate-amy-101-receives-orphan-drug-status-from-the-fda-and-the-ema-for-the-treatment-of-c3-glomerulopathy/ (2019).
182. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03453619 (2019).
183. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03316521 (2018).
184. Noris, M. & Remuzzi, G. Genetics of immune-mediated glomerular diseases: focus on complement. Semin. Nephrol. 37, 447–463 (2017).
185. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03608033 (2019).
186. Mohlin, C., Sandholm, K., Ekdahl, K. N. & Nilsson, B. The link between morphology and complement in ocular disease. Mol. Immunol. 89, 84–99 (2017).
187. Hageman, G. S. 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. USA 102, 7227–7232 (2005).
188. Haines, J. L. et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419–421 (2005).
189. Klein, R. J. et al. Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389 (2005).
190. Schramm, E. C. et al. Genetic variants in the complement system predisposing to age-related macular degeneration: a review. Mol. Immunol. 61, 118–125 (2014).
191. Katschke Jr., K. J. et al. Inhibiting alternative pathway complement activation by targeting the factor D exosite. J. Biol. Chem. 287, 12886–12892 (2012).
192. Yaspan, B. L. et al. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci. Transl Med. 9, eaaf1443 (2017).
193. Irmscher, S. et al. Kallikrein cleaves C3 and activates complement. J. Innate Immun. 10, 94–105 (2017).
194. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01603043 (2014).
195. Chi, Z. L., Yoshida, T., Lambris, J. D. & Iwata, T. 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, 127–135 (2010).
196. Apellis Pharmaceuticals. Apellis Pharmaceuticals announces 18-month results of phase 2 study (FILLY) of APL-2 in geographic atrophy. Apellis Pharmaceuticals http://investors.apellis.com/news-releases/news-release-details/apellis-pharmaceuticals-announces-18-month-results-phase-2-study (2019).
197. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03525613 (2018).
198. Baumann, A., Tuerck, D., Prabhu, S., Dickmann, L. & Sims, J. Pharmacokinetics, metabolism and distribution of PEGs and PEGylated proteins: quo vadis? Drug Discov. Today 19, 1623–1631 (2014).
199. Lyzogubov, V. V., Tytarenko, R. G., Liu, J., Bora, N. S. & Bora, P. S. Polyethylene glycol (PEG)-induced mouse model of choroidal neovascularization. J. Biol. Chem. 286, 16229–16237 (2011).
200. Ruan, C.-C. et al. Complement-mediated macrophage polarization in perivascular adipose tissue contributes to vascular injury in deoxycorticosterone acetate-salt mice. Arterioscler. Thromb. Vasc. Biol. 35, 598–606 (2015).
201. Cao, X. et al. Macrophage polarization in the maculae of age-related macular degeneration: a pilot study. Pathol. Int. 61, 528–535 (2011).
202. Qu, H. et al. New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology 218, 496–505 (2013).
203. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03446144 (2018).
204. Grossman, T. R. et al. Reduction in ocular complement factor B protein in mice and monkeys by systemic administration of factor B antisense oligonucleotide. Mol. Vis. 23, 561–571 (2017).
205. Schnabolk, G. et al. Local production of the alternative pathway component factor B is sufficient to promote laser-induced choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 56, 1850–1863 (2015).
206. Katschke, K. J. et al. Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy. Sci. Rep. 8, 7348 (2018).
207. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00935883 (2017).
208. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01527500 (2019).
209. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02686658 (2018).
210. Botto, M. et al. Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 46, 2774–2783 (2009).
211. Reis, E. S. et al. Safety profile after prolonged C3 inhibition. Clin. Immunol. 197, 96–106 (2018).
212. Konar, M. & Granoff, D. M. Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults. Blood 130, 891–899 (2017).
213. Harris, C. L., Heurich, M., Rodriguez de, C. S. & Morgan, B. P. The complotype: dictating risk for inflammation and infection. Trends Immunol. 33, 513–521 (2012).
214. Gaya da Costa, M. et al. Age and sex-associated changes of complement activity and complement levels in a healthy Caucasian population. Front. Immunol. 9, 2664 (2018). This study illustrates the importance of assessing the impact of gender-specific and age-specific differences on complement activity and protein levels among healthy individuals.
215. Kotimaa, J. et al. Sex matters: systemic complement activity of female C57BL/6J and BALB/cJ mice is limited by serum terminal pathway components. Mol. Immunol. 76, 13–21 (2016).
216. Nilsson, B. & Ekdahl, K. N. Complement diagnostics: concepts, indications, and practical guidelines. Clin. Dev. Immunol. 2012, 962702 (2012).
217. Prohaszka, Z., Nilsson, B., Frazer-Abel, A. & Kirschfink, M. Complement analysis 2016: clinical indications, laboratory diagnostics and quality control. Immunobiology 221, 1247–1258 (2016).
218. Kim, A. H. J. et al. Association of blood concentrations of complement split product iC3b and serum C3 with systemic lupus erythematosus disease activity. Arthritis Rheumatol. 71, 420–430 (2019).
219. Wilson, H. R. et al. Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis. Kidney Int. 95, 655–665 (2019).
220. Thielen, A. J. F. et al. CRISPR/Cas9 generated human CD46, CD55 and CD59 knockout cell lines as a tool for complement research. J. Immunol. Methods 456, 15–22 (2018).
221. Neu, K. E., Tang, Q., Wilson, P. C. & Khan, A. A. Single-cell genomics: approaches and utility in immunology. Trends Immunol. 38, 140–149 (2017).
222. Ugurlar, D. et al. Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement. Science 359, 794–797 (2018).
223. Wang, Q. et al. Identification of a central role for complement in osteoarthritis. Nat. Med. 17, 1674–1679 (2011).
224. Wang, G. et al. Molecular basis of assembly and activation of complement component C1 in complex with immunoglobulin G1 and antigen. Mol. Cell 63, 135–145 (2016).
225. Mortensen, S. A. et al. Structure and activation of C1, the complex initiating the classical pathway of the complement cascade. Proc. Natl Acad. Sci. USA 114, 986–991 (2017).
226. Diebolder, C. A. et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 343, 1260–1263 (2014). This study revealed the structural basis of C1q-mediated classical pathway activation on antibody-targeted surfaces and paved the way for the clinical development of HexaBodies.
227. Cook, E. M. et al. Antibodies that efficiently form hexamers upon antigen binding can induce complement-dependent cytotoxicity under complement-limiting conditions. J. Immunol. 197, 1762–1775 (2016).
228. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03576131 (2019).
229. Woodruff, T. M., Nandakumar, K. S. & Tedesco, F. Inhibiting the C5-C5a receptor axis. Mol. Immunol. 48, 1631–1642 (2011).
230. Liu, H. et al. Orthosteric and allosteric action of the C5a receptor antagonists. Nat. Struct. Mol. Biol. 25, 472–481 (2018).
231. Liszewski, M. K. et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity 39, 1143–1157 (2013).
232. Freeley, S., Kemper, C. & Le, F. G. The ‘ins and outs’ of complement-driven immune responses. Immunol. Rev. 274, 16–32 (2016).
233. Amann, R. I. et al. Toward unrestricted use of public genomic data. Science 363, 350–352 (2019).
234. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).
235. Ajona, D., Ortiz-Espinosa, S. & Pio, R. Complement anaphylatoxins C3a and C5a: emerging roles in cancer progression and treatment. Semin. Cell Dev. Biol. 85, 153–163 (2019).
236. Markiewski, M. M. et al. Modulation of the antitumor immune response by complement. Nat. Immunol. 9, 1225–1235 (2008).
237. Medler, T. R. et al. Complement C5a fosters squamous carcinogenesis and limits T cell response to chemotherapy. Cancer Cell 34, 561–578 (2018).
238. Ajona, D. et al. A combined PD-1/C5a blockade synergistically protects against lung cancer growth and metastasis. Cancer Discov. 7, 694–703 (2017). This study highlights the translational potential of combining targeted complement C5aR1 inhibition with other immunomodulatory therapies in cancer.
239. Zha, H. et al. Blocking C5aR signaling promotes the anti-tumor efficacy of PD-1/PD-L1 blockade. Oncoimmunology 6, e1349587 (2017).
240. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03665129 (2019).
241. Singel, K. L. et al. Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment. JCI Insight 4, e122311 (2019).
242. Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl Med. 9, eaaf6295 (2017).
243. Dejanovic, B. et al. Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies. Neuron 100, 1322–1336 (2018).
244. Nytrova, P. et al. Complement activation in patients with neuromyelitis optica. J. Neuroimmunol. 274, 185–191 (2014).
245. Ramaglia, V. et al. C3-dependent mechanism of microglial priming relevant to multiple sclerosis. Proc. Natl Acad. Sci. USA 109, 965–970 (2012).
246. Fonseca, M. I. et al. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J. Immunol. 183, 1375–1383 (2009).
247. Lee, J. D. et al. Pharmacological inhibition of complement C5a-C5a1 receptor signalling ameliorates disease pathology in the hSOD1G93A mouse model of amyotrophic lateral sclerosis. Br. J. Pharmacol. 174, 689–699 (2017).
248. Woodruff, T. M. et al. The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis. J. Immunol. 181, 8727–8734 (2008).
249. Pittock, S. J. et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 12, 554–562 (2013).
250. Rahpeymai, Y. et al. Complement: a novel factor in basal and ischemia-induced neurogenesis. EMBO J. 25, 1364–1374 (2006).
251. Coulthard, L. G., Hawksworth, O. A. & Woodruff, T. M. Complement: the emerging architect of the developing brain. Trends Neurosci. 41, 373–384 (2018).
252. Orphanet. About rare diseases. Orphanet https://www.orpha.net/consor/cgi-bin/Education_AboutRareDiseases.php (2012).
253. Luzzatto, L. et al. Outrageous prices of orphan drugs: a call for collaboration. Lancet 392, 791–794 (2018). This opinion article raises awareness about the exuberant costs of orphan drugs in clinical practice and points to the adoption of new guidelines and regulations for orphan drug development.
254. Hughes-Wilson, W., Palma, A., Schuurman, A. & Simoens, S. Paying for the orphan drug system: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments? Orphanet J. Rare Dis. 7, 74 (2012).
255. Luzzatto, L. et al. Rare diseases and effective treatments: are we delivering? Lancet 385, 750–752 (2015).
256. Avorn, J. The $2.6 billion pill — methodologic and policy considerations. N. Engl. J. Med. 372, 1877–1879 (2015).
257. Shaughnessy, A. F. Monoclonal antibodies: magic bullets with a hefty price tag. BMJ 345, e8346 (2012).