Download PDF
Transfusionsmedizin 2021; 11(02): 84-99
DOI: 10.1055/a-1145-5522
Übersicht

Komplementinhibitoren: neue Therapeutika – neue Indikationen

Complement Inhibitors: New Drugs – New Indications
Britta Höchsmann
Institut für Klinische Transfusionsmedizin und Immungenetik Ulm, DRK-Blutspendedienst Baden-Württemberg-Hessen und Universitätsklinikum Ulm; Institut für Transfusionsmedizin, Universität Ulm
,
Sixten Körper
Institut für Klinische Transfusionsmedizin und Immungenetik Ulm, DRK-Blutspendedienst Baden-Württemberg-Hessen und Universitätsklinikum Ulm; Institut für Transfusionsmedizin, Universität Ulm
,
Hubert Schrezenmeier
Institut für Klinische Transfusionsmedizin und Immungenetik Ulm, DRK-Blutspendedienst Baden-Württemberg-Hessen und Universitätsklinikum Ulm; Institut für Transfusionsmedizin, Universität Ulm
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Zusammenfassung

Das Komplementsystem, ein klassisch transfusionsmedizinisches Thema, hat in den letzten Jahren in allen Bereichen der Medizin an Bedeutung gewonnen. Komplementinhibitoren werden aufgrund eines besseren Verständnisses der Pathophysiologie unterschiedlicher Erkrankungen in einem sich stetig erweiternden Krankheitsspektrum eingesetzt. Dieses reicht von typisch komplementassoziierten Erkrankungen wie der PNH (paroxysmale nächtliche Hämoglobinurie) bis hin zu akuten Krankheitsbildern mit einer Fehlregulation des Komplementsystems, wie COVID-19.

Abstract

The complement system, a classical transfusion medicine topic, has gained importance in all areas of medicine in recent years. Complement inhibitors are used in a constantly expanding spectrum of diseases due to a better understanding of the pathophysiology of different diseases. This ranges from typical complement-associated diseases such as PNH (paroxysmal nocturnal hemoglobinuria) to acute clinical pictures with a dysregulation of the complement system, such as COVID-19.

Kernaussagen

  • Komplementsystem ist in zahlreiche transfusionsmedizinische wie auch nicht hämotherapeutische pathophysiologische Prozesse involviert

  • Komplementinhibitoren führen bei verschiedenen Erkrankungen zu einem Life-Changing mit hochsignifikanter Steigerung der Lebenserwartung und Lebensqualität

  • Einsatzmöglichkeit von Komplementinhibitoren in der Hämotherapie (z. B. akute und verzögerte Transfusionsreaktion)

  • Differenzierte Komplementtherapeutika stellen eine vielversprechende Behandlungsoption in zahlreichen, unterschiedlichen pathologischen Situationen dar

  • Verschiedene zugelassene Komplementinhibitoren

  • Zahlreiche Komplementmodulatoren auf unterschiedlichen Entwicklungsstufen, um eine bedarfsgerechte krankheitsspezifische Komplementmodulation an der jeweiligen Stufe des Komplementsystems zu ermöglichen

Schlüsselwörter

Komplementsystem - Komplementinhibitoren - Therapeutika

Key words

complement system - complement inhibitor - therapeutics


Publication History

Article published online:
01 June 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Schrezenmeier H, Körper S, Weinstock C. et al. Inhibitoren des Komplementsystems: Erweiterung des therapeutischen Spektrums steht vor der Tür. hämotherapie 2018; 31: 17-28
    PubMedGoogle Scholar
  • 2 Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121: 4985-4996
    CrossrefPubMedGoogle Scholar
  • 3 Pekny M, Wilhelmsson U, Bogestal YR. et al. The role of astrocytes and complement system in neural plasticity. Int Rev Neurobiol 2007; 82: 95-111
    CrossrefPubMedGoogle Scholar
  • 4 Bogestal YR, Barnum SR, Smith PL. et al. Signaling through C5 aR is not involved in basal neurogenesis. J Neurosci Res 2007; 85: 2892-2897
    CrossrefPubMedGoogle Scholar
  • 5 Shinjyo N, Stahlberg A, Dragunow M. et al. Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells 2009; 27: 2824-2832
    CrossrefPubMedGoogle Scholar
  • 6 Stevens B, Allen NJ, Vazquez LE. et al. The classical complement cascade mediates CNS synapse elimination. Cell 2007; 131: 1164-1178
    CrossrefPubMedGoogle Scholar
  • 7 Coulthard LG, Hawksworth OA, Woodruff TM. Complement: The Emerging Architect of the Developing Brain. Trends Neurosci 2018; 41: 373-384
    CrossrefPubMedGoogle Scholar
  • 8 Cekanaviciute E, Buckwalter MS. Astrocytes: Integrative Regulators of Neuroinflammation in Stroke and Other Neurological Diseases. Neurotherapeutics 2016; 13: 685-701
    CrossrefPubMedGoogle Scholar
  • 9 Rooney IA, Oglesby TJ, Atkinson JP. Complement in human reproduction: activation and control. Immunol Res 1993; 12: 276-294
    CrossrefPubMedGoogle Scholar
  • 10 Rooney IA, Atkinson JP, Krul ES. et al. Physiologic relevance of the membrane attack complex inhibitory protein CD59 in human seminal plasma: CD59 is present on extracellular organelles (prostasomes), binds cell membranes, and inhibits complement-mediated lysis. J Exp Med 1993; 177: 1409-1420
    CrossrefPubMedGoogle Scholar
  • 11 Simpson KL, Holmes CH. Differential expression of complement regulatory proteins decay-accelerating factor (CD55), membrane cofactor protein (CD46) and CD59 during human spermatogenesis. Immunology 1994; 81: 452-461
    PubMedGoogle Scholar
  • 12 Oglesby TJ, Longwith JE, Huettner PC. Human complement regulator expression by the normal female reproductive tract. Anat Rec 1996; 246: 78-86
    CrossrefPubMedGoogle Scholar
  • 13 Teisner B, Grudzinskas JG. Complement activation during normal pregnancy. Placenta Suppl 1982; 4: 119-124
    PubMedGoogle Scholar
  • 14 Grudzinskas JG, Teisner B. Pregnancy proteins and activation of the complement system. Placenta Suppl 1982; 4: 115-118
    PubMedGoogle Scholar
  • 15 Jenkins JS, Powell RJ. C3 degradation products (C3d) in normal pregnancy. J Clin Pathol 1987; 40: 1362-1363
    CrossrefPubMedGoogle Scholar
  • 16 Faulk WP, Jarret R, Keane M. et al. Immunological studies of human placentae: complement components in immature and mature chorionic villi. Clin Exp Immunol 1980; 40: 299-305
    PubMedGoogle Scholar
  • 17 McCormick JN, Faulk WP, Fox H. et al. Immunohistological and elution studies of the human placenta. J Exp Med 1971; 133: 1-18
    CrossrefPubMedGoogle Scholar
  • 18 Girardi G. Complement activation, a threat to pregnancy. Semin Immunopathol 2018; 40: 103-111
    CrossrefPubMedGoogle Scholar
  • 19 Soto E, Romero R, Richani K. et al. Preeclampsia and pregnancies with small-for-gestational age neonates have different profiles of complement split products. J Matern Fetal Neonatal Med 2010; 23: 646-657
    CrossrefPubMedGoogle Scholar
  • 20 Ghebrehiwet B, Peerschke EI. Complement and coagulation: key triggers of COVID-19-induced multiorgan pathology. J Clin Invest 2020; 130: 5674-5676
    CrossrefPubMedGoogle Scholar
  • 21 Rambaldi A, Gritti G, Mico MC. et al. Endothelial injury and thrombotic microangiopathy in COVID-19: Treatment with the lectin-pathway inhibitor narsoplimab. Immunobiology 2020; 225: 152001
    CrossrefPubMedGoogle Scholar
  • 22 Watkins WM, Wormall A. Inactivation of complement by nitrogen mustard. Nature 1948; 162: 535
    CrossrefPubMedGoogle Scholar
  • 23 Watkins WM, Wormall A. The action, in vitro and in vivo, of some nitrogen mustards on haemolytic complement. Biochem J 1952; 52: 365-377
    CrossrefPubMedGoogle Scholar
  • 24 Cushman WF, Becker EL, Wirtz G. Concerning the mechanism of complement action. III. Inhibitors of complement activity. J Immunol 1957; 79: 80-83
    CrossrefPubMedGoogle Scholar
  • 25 Jensen JA, Garces MC, Iglesias E. Specific inactivation of the fourth complement component. I. In vivo studies. Infect Immun 1971; 4: 12-19
    CrossrefPubMedGoogle Scholar
  • 26 Luzzatto L. Paroxysmal nocturnal hemoglobinuria: an acquired X-linked genetic disease with somatic-cell mosaicism. Curr Opin Genet Dev 2006; 16: 317-322
    CrossrefPubMedGoogle Scholar
  • 27 Hernandez-Campo PM, Almeida J, Acevedo MJ. et al. Detailed immunophenotypic characterization of different major and minor subsets of peripheral blood cells in patients with paroxysmal nocturnal hemoglobinuria. Transfusion 2008; 48: 1403-1414
    CrossrefPubMedGoogle Scholar
  • 28 Richards SJ, Hillmen P. Immunophenotypic analysis of PNH cells. Curr Protoc Cytom 2002; Chapter 6: Unit6.11 DOI: 10.1002/0471142956.cy0611s20.
    CrossrefPubMedGoogle Scholar
  • 29 Nebe T, Schubert J. et al. Flow cytometric analysis of GPI-deficient cells for the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). J Lab Med 2003; 27: 257-265
    PubMedGoogle Scholar
  • 30 Hochsmann B, Rojewski M, Schrezenmeier H. Paroxysmal nocturnal hemoglobinuria (PNH): higher sensitivity and validity in diagnosis and serial monitoring by flow cytometric analysis of reticulocytes. Ann Hematol 2011; 90: 887-899
    CrossrefPubMedGoogle Scholar
  • 31 Hillmen P, Lewis SM, Bessler M. et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333: 1253-1258
    CrossrefPubMedGoogle Scholar
  • 32 de Latour RP, Mary JY, Salanoubat C. et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008; 112: 3099-3106
    CrossrefPubMedGoogle Scholar
  • 33 Hillmen P, Muus P, Duhrsen U. et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110: 4123-4128
    CrossrefPubMedGoogle Scholar
  • 34 De Stefano V, Rossi E, Paciaroni K. et al. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002; 87: 1095-1108
    PubMedGoogle Scholar
  • 35 Weitz IC. Thrombosis in Paroxysmal Nocturnal Hemoglobinuria – insights into the role of complement in thrombosis. Thromb Res 2010; 125 (Suppl. 02) S106-S107
    CrossrefPubMedGoogle Scholar
  • 36 McKeage K. Eculizumab: a review of its use in paroxysmal nocturnal haemoglobinuria. Drugs 2011; 71: 2327-2345
    CrossrefPubMedGoogle Scholar
  • 37 Kristiansen M, Graversen JH, Jacobsen C. et al. Identification of the haemoglobin scavenger receptor. Nature 2001; 409: 198-201
    CrossrefPubMedGoogle Scholar
  • 38 Olson JS, Foley EW, Rogge C. et al. NO scavenging and the hypertensive effect of hemoglobin-based blood substitutes. Free Radic Biol Med 2004; 36: 685-697
    CrossrefPubMedGoogle Scholar
  • 39 Schnog JJ, Jager EH, van der Dijs FP. et al. Evidence for a metabolic shift of arginine metabolism in sickle cell disease. Ann Hematol 2004; 83: 371-375
    CrossrefPubMedGoogle Scholar
  • 40 Hill A, Rother RP, Wang X. et al. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2010; 149: 414-425
    CrossrefPubMedGoogle Scholar
  • 41 Brodsky RA, Young NS, Antonioli E. et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111: 1840-1847
    CrossrefPubMedGoogle Scholar
  • 42 Hillmen P, Hall C, Marsh JC. et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004; 350: 552-559
    CrossrefPubMedGoogle Scholar
  • 43 Hill A, Hillmen P, Richards SJ. et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 2005; 106: 2559-2565
    CrossrefPubMedGoogle Scholar
  • 44 Harder MJ, Kuhn N, Schrezenmeier H. et al. Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood 2017; 129: 970-980
    CrossrefPubMedGoogle Scholar
  • 45 Hill A, Rother RP, Arnold L. et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010; 95: 567-573
    CrossrefPubMedGoogle Scholar
  • 46 Hochsmann B, Leichtle R, von Zabern I. et al. Paroxysmal nocturnal haemoglobinuria treatment with eculizumab is associated with a positive direct antiglobulin test. Vox Sang 2012; 102: 159-166
    CrossrefPubMedGoogle Scholar
  • 47 Risitano AM, Notaro R, Luzzatto L. et al. Paroxysmal nocturnal hemoglobinuria–hemolysis before and after eculizumab. N Engl J Med 2010; 363: 2270-2272
    CrossrefPubMedGoogle Scholar
  • 48 Helley D, de Latour RP, Porcher R. et al. Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Haematologica 2010; 95: 574-581
    CrossrefPubMedGoogle Scholar
  • 49 Kelly RJ, Hill A, Arnold LM. et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011; 117: 6786-6792
    CrossrefPubMedGoogle Scholar
  • 50 Socie G, Schrezenmeier H, Muus P. et al. Changing prognosis in paroxysmal nocturnal haemoglobinuria disease subcategories: an analysis of the International PNH Registry. Intern Med J 2016; 46: 1044-1053
    CrossrefPubMedGoogle Scholar
  • 51 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 1676-1687
    CrossrefPubMedGoogle Scholar
  • 52 Nurnberger J, Philipp T, Witzke O. et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 2009; 360: 542-544
    CrossrefPubMedGoogle Scholar
  • 53 Licht C, Greenbaum LA, Muus P. et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 2015; 87: 1061-1073
    CrossrefPubMedGoogle Scholar
  • 54 Howard jr. JF, Utsugisawa K, Benatar M. 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 2017; 16: 976-986
    CrossrefPubMedGoogle Scholar
  • 55 Biglarnia AR, Nilsson B, Nilsson T. et al. Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation. Transpl Int 2011; 24: e61-e66
    CrossrefPubMedGoogle Scholar
  • 56 West-Thielke P, Progar K, Campara M. et al. Eculizumab for Prevention of Antibody-Mediated Rejection in Blood Group-Incompatible Renal Transplantation. Transplant Proc 2018; 50: 66-69
    CrossrefPubMedGoogle Scholar
  • 57 Lanfranco L, Joly M, Del BA. et al. Eculizumab for Thrombotic Microangiopathy Associated with Antibody-Mediated Rejection after ABO-Incompatible Kidney Transplantation. Case Rep Transplant 2017; 2017: 3197042 DOI: 10.1155/2017/3197042.
    CrossrefPubMedGoogle Scholar
  • 58 Burwick RM, Fichorova RN, Dawood HY. et al. Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. Hypertension 2013; 62: 1040-1045
    CrossrefPubMedGoogle Scholar
  • 59 Shapira I, Andrade D, Allen SL. et al. Brief report: induction of sustained remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum 2012; 64: 2719-2723
    CrossrefPubMedGoogle Scholar
  • 60 Bommer M, Höchsmann B, Flegel W. et al. Succesful treatment of complement mediated refractory hemolysis associated with cold and warm autoantibodies using eculizumab. Haematologica 2011; 94 (Suppl. 02) 241 abs. 0593
    PubMedGoogle Scholar
  • 61 Röth A, Bommer M, Hüttmann A. et al. Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial). Blood 2016; 126: 274
    CrossrefPubMedGoogle Scholar
  • 62 Dumas G, Habibi A, Onimus T. et al. Eculizumab salvage therapy for delayed hemolysis transfusion reaction in sickle cell disease patients. Blood 2016; 127: 1062-1064
    CrossrefPubMedGoogle Scholar
  • 63 Gupta S, Fenves A, Nance ST. et al. Hyperhemolysis syndrome in a patient without a hemoglobinopathy, unresponsive to treatment with eculizumab. Transfusion 2015; 55: 623-628
    CrossrefPubMedGoogle Scholar
  • 64 Urwyler P, Moser S, Charitos P. et al. Treatment of COVID-19 With Conestat Alfa, a Regulator of the Complement, Contact Activation and Kallikrein-Kinin System. Front Immunol 2020; 11: 2072
    CrossrefPubMedGoogle Scholar
  • 65 Laurence J, Mulvey JJ, Seshadri M. et al. Anti-complement C5 therapy with eculizumab in three cases of critical COVID-19. Clin Immunol 2020; 219: 108555
    CrossrefPubMedGoogle Scholar
  • 66 Giudice V, Pagliano P, Vatrella A. et al. Combination of Ruxolitinib and Eculizumab for Treatment of Severe SARS-CoV-2-Related Acute Respiratory Distress Syndrome: A Controlled Study. Front Pharmacol 2020; 11: 857
    CrossrefPubMedGoogle Scholar
  • 67 Anliker M, Schmidt CQ, Harder MJ. et al. Complement activation by human anti-red cell antibodies: hemolytic potential of antibodies and efficacy of complement inhibitors assessed by a sensitive flow cytometric assay. Transfusion 2018; 58: 2992-3002
    CrossrefPubMedGoogle Scholar
  • 68 Sheridan D, Yu ZX, Zhang Y. et al. Design and preclinical characterization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS One 2018; 13: e0195909
    CrossrefPubMedGoogle Scholar
  • 69 Brodsky RA, Peffault de LR, Rottinghaus ST. et al. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica 2021; 106: 230-237
    CrossrefPubMedGoogle Scholar
  • 70 Roth A, Rottinghaus ST, Hill A. et al. Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv 2018; 2: 2176-2185
    CrossrefPubMedGoogle Scholar
  • 71 Schrezenmeier H, Kulasekararaj AG, Mitchell L. One-year Efficacy of Ravulizumab (ALXN1210) n adult patients with paroxysmal nocturnal Hemoglobinuria naive to complement inhibitors. EHA Learning Center EHA Meeting 2019. Im Internet (Stand: 12.05.2021): https://library.ehaweb.org/eha/2019/24th/267446/hubert.schrezenmeier.one-year.efficacy.of.ravulizumab.28alxn121029.in.adult.html
    PubMedGoogle Scholar
  • 72 Lee JW, Rottinghaus ST, Lee Lee LW. et al. Results from a phase 3, multicenter, noninferiority study of Ravulizumab (ALXN1210) versus Eculizumab in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) naive to complement inhibitors. EHA Learning Center Jun 17, 2018; 218885. 2018 Im Internet (Stand: 12.05.2021): https://library.ehaweb.org/eha/2018/stockholm/218885/jong.wook.lee.results.from.a.phase.3.multicenter.noninferiority.study.of.html
    PubMedGoogle Scholar
  • 73 Peipert JD, Kulasekararaj AG, Gaya A. et al. Patient preferences and quality of life implications of ravulizumab (every 8 weeks) and eculizumab (every 2 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria. PLoS One 2020; 15: e0237497
    CrossrefPubMedGoogle Scholar
  • 74 Roth A, Nishimura JI, Nagy Z. et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood 2020; 135: 912-920
    CrossrefPubMedGoogle Scholar
  • 75 Fukuzawa T, Sampei Z, Haraya K. et al. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci Rep 2017; 7: 1080
    CrossrefPubMedGoogle Scholar
  • 76 Kassa E, Ciulla TA, Hussain RM. et al. Complement inhibition as a therapeutic strategy in retinal disorders. Expert Opin Biol Ther 2019; 19: 335-342
    CrossrefPubMedGoogle Scholar
  • 77 Zelek WM, Cole J, Ponsford MJ. et al. Complement Inhibition with the C5 Blocker LFG316 in Severe COVID-19. Am J Respir Crit Care Med 2020; 202: 1304-1308
    CrossrefPubMedGoogle Scholar
  • 78 Chow V, Pan J, Chien D. et al. A randomized, double-blind, single-dose, three-arm, parallel group study to determine pharmacokinetic similarity of ABP 959 and eculizumab (Soliris®) in healthy male subjects. Eur J Haematol 2020; 105: 66-74
    CrossrefPubMedGoogle Scholar
  • 79 Nunn MA, Sharma A, Paesen GC. et al. Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. J Immunol 2005; 174: 2084-2091
    CrossrefPubMedGoogle Scholar
  • 80 Hill A, Wyndiga J, Robak T. et al. Results of COBALT, a phase II clinical trial of Coversin in PNH. EHA Learning Center Jun 15, 2018; 214790. 2018 Im Internet (Stand: 12.05.2021): https://library.ehaweb.org/eha/2018/stockholm/214790/anita.hill.results.of.cobalt.a.phase.ii.clinical.trial.of.coversin.in.pnh.html
    PubMedGoogle Scholar
  • 81 Kulasekararaj A, Weston-Davies W, Robak T. et al. Long Term Nomacopan Administration Results in Complete Transfusion Independence in Previously Transfusion-Dependent PNH Patients. Blood 2019; 134 (Suppl. 01) 4797 DOI: 10.1182/blood-2019-125263.
    CrossrefPubMedGoogle Scholar
  • 82 Latuszek A, Liu Y, Olsen O. et al. Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5. PLoS One 2020; 15: e0231892
    CrossrefPubMedGoogle Scholar
  • 83 Ricardo A, Arata M, DeMarco S. Preclinical Evaluation of RA101495, a Potent Cyclic Peptide Inhibitor of C5 for the Treatment of Paroxysmal Nocturnal Hemoglobinuria. Blood 2015; 126: 939
    CrossrefPubMedGoogle Scholar
  • 84 Gorman DM, Lee J, Payne CD. et al. Chemical synthesis and characterisation of the complement C5 inhibitory peptide zilucoplan. Amino Acids 2021; 53: 143-147
    CrossrefPubMedGoogle Scholar
  • 85 Hill A, Schrezenmeier H, Hillmen P. et al. RA101495, A subcutaneously-administered peptide inhibitor of complement component C5, for the treatment of paroxysmal nocturnal hemoglobinuria: phase 2 results. EHA Learning Center. Jun. 15, 2018; 214782. 2018. Im Internet (Stand: 12.05.2021): https://library.ehaweb.org/eha/2018/stockholm/214782/anita.hill.ra101495.a.subcutaneously-administered.peptide.inhibitor.of.html
    PubMedGoogle Scholar
  • 86 Hill A, Valls AG, Griffin M. 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 2016; 128: 3891
    CrossrefPubMedGoogle Scholar
  • 87 Kusner LL, Yucius K, Sengupta M. et al. Investigational RNAi Therapeutic Targeting C5 Is Efficacious in Pre-clinical Models of Myasthenia Gravis. Mol Ther Methods Clin Dev 2019; 13: 484-492
    CrossrefPubMedGoogle Scholar
  • 88 Jang JH, Hill A, Mingh-Dauh YGN. et al. Pozelimab inhibits hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). [EHA Library 2020]. 2021 Im Internet (Stand: 12.05.2021): https://library.ehaweb.org/eha/2020/eha25th/294777/jun-ho.jang.pozelimab.inhibits.hemolysis.in.patients.with.paroxysmal.nocturnal.html
    PubMedGoogle Scholar
  • 89 Jager U, DʼSa S, Schorgenhofer C. et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood 2019; 133: 893-901
    CrossrefPubMedGoogle Scholar
  • 90 Broome CM, Röth A, Kuter D. et al. Inhibition of the classical complement pathway with Sutimlimab in patients with chronic immune thrombocytopenia without adequate response to two or more prior therapies. EHA Library 06/12/20; 294112; EP1630. 2020 Im Internet (Stand: 12.05.2021): https://library.ehaweb.org/eha/2020/eha25th/294112/catherine.m.broome.inhibition.of.the.classical.complement.pathway.with.html
    PubMedGoogle Scholar
  • 91 Nikitin PA, Rose EL, Byun TS. et al. C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro. J Immunol 2019; 202: 1200-1209
    CrossrefPubMedGoogle Scholar
  • 92 Gertz MA, Qiu H, Kendall L. et al. ANX005, an inhibitory antibody against C1q, blocks complement activation triggered by cold agglutinins in human disease. Blood 2016; 128: 1265 DOI: 10.1182/blood.V128.22.1265.1265.
    CrossrefPubMedGoogle Scholar
  • 93 Van de Walle I, Silence K, Budding K. et al. ARGX-117, a therapeutic complement inhibiting antibody targeting C2. J Allergy Clin Immunol 2021; 147: 1420-1429.e7
    CrossrefPubMedGoogle Scholar
  • 94 Schubart A, Anderson K, Mainolfi N. et al. Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci U S A 2019; 116: 7926-7931
    CrossrefPubMedGoogle Scholar
  • 95 Risitano AM, Kulasekararaj AG, Lee JW. et al. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica 2020; DOI: 10.3324/haematol.2020.261826.
    CrossrefPubMedGoogle Scholar
  • 96 Kulasekararaj A, Risitano A, Lee JW. et al. Phase 3 Study of Danicopan, an Oral Complement Factor D Inhibitor, As Add-on Therapy to a C5 Inhibitor in Patients with Paroxysmal Nocturnal Hemoglobinuria with Clinically Evident Extravascular Hemolysis. Blood 2020; 136 (Suppl. 01) 6-7 DOI: 10.1182/blood-2020-134388.
    CrossrefPubMedGoogle Scholar
  • 97 Wiles JA, Galvan MD, Podos SD. et al. Discovery and Development of the Oral Complement Factor D Inhibitor Danicopan (ACH-4471). Curr Med Chem 2020; 27: 4165-4180
    CrossrefPubMedGoogle Scholar
  • 98 Fridkis-Hareli M, Storek M, Mazsaroff I. 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 2011; 118: 4705-4713
    CrossrefPubMedGoogle Scholar
  • 99 Risitano AM, Notaro R, Pascariello C. et al. The complement receptor 2/factor H fusion protein TT30 protects paroxysmal nocturnal hemoglobinuria erythrocytes from complement-mediated hemolysis and C3 fragment. Blood 2012; 119: 6307-6316
    CrossrefPubMedGoogle Scholar
  • 100 Chen JY, Cortes C, Ferreira VP. Properdin: A multifaceted molecule involved in inflammation and diseases. Mol Immunol 2018; 102: 58-72
    CrossrefPubMedGoogle Scholar
  • 101 Chen JY, Galwankar NS, Emch HN. et al. Properdin Is a Key Player in Lysis of Red Blood Cells and Complement Activation on Endothelial Cells in Hemolytic Anemias Caused by Complement Dysregulation. Front Immunol 2020; 11: 1460
    CrossrefPubMedGoogle Scholar
  • 102 Sahu A, Kay BK, Lambris JD. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J Immunol 1996; 157: 884-891
    CrossrefPubMedGoogle Scholar
  • 103 de Castro C, Grossi F, Weitz IC. et al. C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab. Am J Hematol 2020; 95: 1334-1343
    CrossrefPubMedGoogle Scholar
  • 104 Hillmen P, Szer J, Weitz I. et al. Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med 2021; 384: 1028-1037
    CrossrefPubMedGoogle Scholar
  • 105 Peffault De Latour R, de Castro CM, Szer J. et al. Pegcetacoplan Is Superior to Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Regardless of Prior Transfusion Requirement. Blood; 2020; 136 (Suppl. 01) 32-33 DOI: 10.1182/blood-2020-141061.
    CrossrefPubMedGoogle Scholar
  • 106 Wong RS, Ignatova K, Pullon H. et al. C3 Inhibition with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from the Paddock and Palomino Trials. Blood 2020; 136 (Suppl. 01) 3-4 DOI: 10.1182/blood-2020-134436.
    CrossrefPubMedGoogle Scholar