Современные и разрабатываемые биотехнологические препараты для лечения патологии системы комплемента при пароксизмальной ночной гемоглобинурии

Пароксизмальная ночная гемоглобинурия (ПНГ) – это редкое приобретенное клональное заболевание крови, развивающееся в результате соматической мутации гена фосфатидилинозитол гликана класса А (PIG-A) в стволовых кроветворных клетках и проявляющееся гемолитической анемией, костномозговой недостаточностью, тромбозами, нарушением функции почек и другими тяжелыми клиническими синдромами. Лечение ПНГ является сложной клинической задачей, требующей комплексного подхода. В последнее десятилетие таргетная терапия с применением ингибитора терминального этапа активации комплемента антитела экулизумаб играет ключевую роль в лечении ПНГ. Экулизумаб является первым гуманизированным моноклональным анти-С5-антителом, подтвердившим эффективное ингибирование системы комплемента и одобренным во многих странах в качестве стандарта лечения ПНГ. С 2019 г. в Российской Федерации широко используется для лечения ПНГ первый биоаналог экулизумаба (Элизария), подтвердивший в ходе клинических исследований аналогичные оригинальному препарату эффективность и безопасность. В настоящее время продолжаются разработки новых препаратов ингибиторов комплемента, которые подразделяются по механизму действия на ингибиторы C5-компонента комплемента (терминальная часть) и ингибиторы ранних фаз каскада комплемента (проксимальная часть). К новым препаратам относятся моноклональные антитела, малые молекулы, небольшие пептидные ингибиторы и малые интерферирующие РНК, а также рекомбинантные белки, полученные на основе эндогенных регуляторов активации комплемента.

система комплемента, пароксизмальная ночная гемоглобинурия, комплементопосредованный гемолиз, антикомплементарная терапия, экулизумаб, биоаналоги, моноклональные антитела

1. Кулагин А.Д., Лисуков И.А., Птушкин В.В., Шилова Е.Р., Цветаева Н.В., Михайлова Е.А. Национальные клинические рекомендации по диагностике и лечению пароксизмальной ночной гемоглобинурии. Клиническая фармакология и терапия 2015; 24 (1): 18–26.

2. Brodsky R.A. Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124 (18): 2804–11. DOI: 10.1182/blood-2014-02-522128

3. Hill A., DeZern A.E., Kinoshita T., Brodsky R.A. Paroxysmal nocturnal hemoglobinuria. Nat Rev Dis Primers 2017; 18 (3): 17028. DOI: 10.1038/nrdp.2017.28

4. Socie G., Schrezenmeier H., Muus P., Lisukov I., Roth A., Kulasekararaj A., et al. Changing prognosis in paroxysmal nocturnal hemoglobinuria disease subcategories: an analysis of the International PNH Registry. Intern Med J 2016; 46 (9): 1044–53. DOI: 10.1111/imj.13160

5. Johnson R., Hillmen P. Paroxysmal nocturnal haemoglobinuria: Nature’s gene therapy? J Clin Pathol: Mol Pathol 2002; 55 (3): 145−52. DOI: 10.1136/mp.55.3.145

6. Kinoshita T. Congenital defects in the expression of the glycosylphosphatidylinositol-anchored complement regulatory proteins CD59 and decay-accelerating factor. Semin. Hematol. 2018; 55 (3): 136–40. DOI: 10.1053/j.seminhematol.2018.04.004

7. Parker C., Omine M., Richards S., Nishimura J.-I., Bessler M., Ware R., et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106 (12): 3699–709. DOI: 10.1182/blood-2005-04-1717

8. Parker C.J. Update on the Diagnosis and Management of Paroxysmal Nocturnal Hemoglobinuria. Hematology Am Soc Hematol Educ Program 2016; 2016 (1): 208–16. DOI: 10.1182/asheducation-2016.1.208

9. Hillmen P., Lewis S.M., Bessler M., Luzzatto L., Dacie J.V. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333 (19): 1253–8. DOI: 10.1056/NEJM199511093331904

10. Hill A., Kelly R.J., Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121 (25): 4985–96; quiz 5105.DOI: 10.1182/blood-2012-09-311381

11. Weitz I.C. Thrombosis in patients with paroxysmal nocturnal hemoglobinuria. Semin Thromb Hemost 2011; 37 (3): 315–21. DOI: 10.1055/s-0031-1273095

12. Hillmen P., Muus P., Duhrsen U., Risitano A.M., Schubert J., Luzzatto L., et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110 (12): 4123–8. DOI: 10.1182/blood-2007-06-095646

13. Moyo V.M., Mukhina G.L., Garrett E.S., Brodsky R.A. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol 2004; 126 (1): 133–8. DOI: 10.1111/j.1365-2141.2004.04992.x

14. Hill A., Rother R.P., Wang X., Morris S.M. Jr, Quinn-Senger K., Kelly R., 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 (3): 414–25. DOI: 10.1111/j.1365-2141.2010.08096.x

15. Hillmen P., Elebute M., Kelly R., Urbano-Ispizua A., Hill A., Rother R.P., et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol 2010; 85 (8): 553–9. DOI: 10.1002/ajh.21757

16. Sakurai M., Jang J.H., Chou W.-C., Kim J.S., Wilson A., Nishimura J.-I., et al. Comparative study on baseline clinical characteristics of Asian versus nonAsian patients with paroxysmal nocturnal hemoglobinuria / International Journal of Hematology October 2019; 110 (4): 411– 8. DOI: 10.1007/s12185-019-02699-7

17. Кулагин А.Д. Пароксизмальная ночная гемоглобинурия: современные представления о редком заболевании. Клиническая онкогематология 2019; 12 (1): 4–20.

18. Brodsky R.A., Young N.S., Antonioli E., Risitano A.M., Schrezenmeier H., Schubert J., et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008; 111 (4): 1840–7. DOI: 10.1182/blood-2007-06-094136

19. European Medicines Agency (EMA). Soliris: EPAR – Product Information. Summary of product characteristics. London: EMA; 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/soliris#product-information-section

20. Эмирова Х.М., Орлова О.М., Музуров А.Л., Генералова Г.А., Панкратенко Т.Е., Абасеева Т.Ю. и др. Опыт применения Элизарии® при атипичном гемолитико-уремическом синдроме. Педиатрия 2019; 98 (5): 225–9.

21. Lavrishcheva I.V., Jakovenko A.A., Kudlay D.A. A case report of atypical hemolytic-uremic syndrome treatment with the first Russian eculizumab in adult patient. Urology & Nephrology Open Access Journal 2020; 8 (2): 37–40.

22. Kulagin A., Ptushkin V., Lukina E., Gapchenko E., Markova O., Zuev E., Kudlay D. Phase III clinical trial of Elizaria® and Soliris® in adult patients with paroxysmal nocturnal hemoglobinuria: results of comparative analysis of efficacy, safety, and pharmacological data. Blood 2019; 134 (Suppl 1): 3748. DOI: 10.1182/blood2019-125693

23. Птушкин В.В., Кулагин А.Д., Лукина Е.А., Давыдкин И.Л., Константинова Т.С., Шамрай В.С. и др. Результаты открытого многоцентрового клинического исследования Ib фазы по оценке безопасности, фармакокинетики и фармакодинамики первого биоаналога экулизумаба у нелеченых пациентов с пароксизмальной ночной гемоглобинурией в фазе индукции терапии. Терапевтический архив 2020; 92 (7): 77–84. DOI: 10.26442/00403660.2020.07.000818.

24. Иванов Р., Секарёва Г., Кравцова О., Кудлай Д., Лукьянов С., Тихонова И. и др. Правила проведения исследований биоаналоговых лекарственных средств (биоаналогов). Фармакокинетика и фармакодинамика 2014; 1: 21–36.

25. Risitano A., Marotta S. Toward complement inhibition 2.0: Next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria. Am J Hematol 2018; 93 (4): 564–77. DOI: 10.1002/ajh.25016

26. Mastellos D., Ricklin D., Lambris J. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 2019; 18 (9): 707–29. DOI: 10.1038/s41573-019-0031-6

27. Sheridan D., Yu Z.X., Zhang Y., Patel R., Sun F., Lasaro M.A., et al. Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action. PLoS ONE 2018; 13: e0195909. DOI: 10.1371/journal.pone.0195909

28. A Phase 1/2 Study of an Investigational Drug, ALN-CC5, in Healthy Adult Volunteers and Patients With PNH. ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02352493

29. Kulasekararaj A.G., Hill A., Rottinghaus S.T., Langemeijer S., Wells R., Gonzalez-Fernandez F.A., et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood 2019; 133 (6): 540– 9. DOI: 10.1182/blood-2018-09-876805

30. Kulasekararaj A. Hill A.J., Langemeijer S., Wells R.A., González-Fernández F., Gayà A., et al. One-Year Efficacy and Safety from a Phase 3 Trial of Ravulizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Receiving Prior Eculizumab Treatment. Blood 2019; 134 (Suppl 1): 2231.

31. Fukuzawa T., Sampei Z., Haraya K., Ruike Y., Shida-Kawazoe M., Shimizu Y., 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. DOI: 10.1038/s41598-017-01087-7

32. Sampei Z., Haraya K., Tachibana T., Fukuzawa T., Shida-Kawazoe M., Gan S.W., et al. Antibody engineering to generate SKY59, a long-acting anti-C5 recycling antibody. PLoS ONE 2018; 13: e0209509. DOI:10.1371/journal.pone.0209509

33. Roth A., Egyed M., Ichikawa S., Kim J.S., Nagy Z., Weisinger J.G., et al. The SMART Anti-hC5 antibody (SKY59/ RO7112689) shows good safety and efficacy in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Blood 2018; 132: 535. DOI: 10.1182/blood-2018-99-113274

34. Peffault de Latour R., Schrezenmeier H., Bacigalupo A., Blaise D., de Souza C.A., Vigouroux S., et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 2012; 97:1666–73. DOI: 10.3324/haematol.2012.062828

35. Sostelly A., Soubret A., Bucher C., Buatois S., Charoin j.e., Jordan G., et al. Characterizing C5 Inhibition with the SMART-Ig Anti-hC5 Antibody Crovalimab in PNH Patients Using Free Available Paratopes. Blood 2019; 134 (Suppl 1): 1227. DOI: 10.1182/blood-2019-126911

36. Röth A., Nishimura J.-I. , Nagy Z., GaàlWeisinger J., Panse J., Yoon S.-S., et al. The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood 2020; 135 (12): 912–20. DOI: 10.1182/blood.2019003399

37. Proof of Concept Study to Assess the Efficacy, Safety and Pharmacokinetics of LFG316 in Patients with Paroxysmal Nocturnal Hemoglobinuria. ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02534909

38. Nishimura J., Yamamoto M., Hayashi S., Ohyashiki K., Ando K., Brodsky A.L., et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med 2014; 370 (7): 632–9. DOI: 10.1056/NEJMoa1311084

39. Weyne J., Ni Y., DelGizzi R., Godin S., Morton L., Prasad S., et al. A randomized, double-blind, placebo-controlled phase 1 study of the pharmacokinetics and pharmacodynamics of REGN3918, a human antibody against complement factor C5, in healthy volunteers. Blood 2018; 132: 1039. DOI: 10.1182/blood-2018-99-112262

40. A Randomized, Double-Blind, Active-Controlled Phase 3 Study Evaluating the Efficacy and Safety Of Abp 959 Compared With Eculizumab in Adult Subjects With Paroxysmal Nocturnal Hemoglobinuria (PNH). EU Clinical Trials Register. Available at: https://www.clinicaltrialsregister.eu/ctrsearch/search?query=2017--001418-27

41. Josephson K., Ricardo A., Szostak J.W. mRNA display: from basic principles to macrocycle drug discovery. Drug Discov Today 2014; 19: 388–99. DOI: 10.1016/j.drudis.2013.10.011

42. Ricardo A., Arata M., DeMarco S., Dhamnaskar K., Hammer R., Fridkis-Hareli M., et al. Preclinical evaluation of RA101495, a potent cyclic peptide inhibitor of C5 for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 2015; 126: 939.

43. Phase 2 Safety and Efficacy Study of Zilucoplan (RA101495) to Treat PNH Patients ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/results/NCT03078582?term=RA101495&draw=2&rank=3

44. Ricardo A., Hoarty M.D., Blain J.C., DeMarco S.J., Galullo V., Hale M.R., et al. Discovery of orally bioavailable small molecules for inhibition of complement C5. Haematologica 2017; 102: 189.

45. Ricardo A., Hale M., Zhong M., Reves J., Savegh C., Sherry K., et al. Characterization or orally bioavailable small molecule inhibitirs of complement C5. HemaSphere 2018; 2: 730.

46. Nunn M.A., Sharma A., Paesen G.C., Adamson S., Lissina O., Willis A.C., et al. Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata. J Immunol 2005; 174: 2084–91. DOI: 10.4049/jimmunol.174.4.2084

47. Weston-Davies W.H., Nunn M.A., Pinto F.O., Mackie I.J., Richards S.J., Machin S.J., et al. Clinical and immunological characterisation of coversin, a novel small protein inhibitor of complement C5 with potential as a therapeutic agent in PNH and other complement mediated disorders. Blood 2014; 124: 4280.

48. Coversin in Paroxysmal Nocturnal Haemoglobinuria (PNH) in Patients with resistance to eculizumab due to complement C5 polymorphisms. ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02591862

49. COBALT: Coversin Global Study: An Open-Label, Safety and Efficacy Trial in PNH Patients. EU Clinical Trials Register. Available at: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016--002067-33

50. Hill A., Windyga J., Robak T., Hellman A., Kulasekararaj A., Weston-Daview W., et al. Results of COBALT, a phase II clinical trial of coversin in PNH. HemaSphere 2018; 2: 109.

51. Borodovsky A., Yucius K., Sprague A., Butler J., Fishman S., Nguyen T., et al. Development Of RNAi therapeutics targeting the complement pathway. Blood 2013; 122: 2471.

52. Hill A., Taubel J., Bush J., Borodovsky A., Kawahata N., Mclean H., et al. A subcutaneously administered investigational RNAi therapeutic (ALN-CC5) targeting complement C5 for treatment of PNH and complement-mediated diseases: interim phase 1 study results. Blood 2015; 126: 2413.

53. Hill A., Valls A.G., Griffin M., Munir T., Borodovsky A., Kawahata N., 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.

54. A Phase 2, Open-label, Single Dose, Study of Subcutaneously Administered ALN-CC5 in Patients with Paroxysmal Nocturnal Hemoglobinuria who are Inadequate Responders to Eculizumab. EU Clinical Trials Register. Available online at: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2016--002943-40

55. Risitano A.M., Notaro R., Marando L., Serio B., Ranaldi D., Seneca E., et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 2009; 113: 4094–100. DOI: 10.1182/blood-2008-11-189944

56. Hill A., Rother R.P., Arnold L., Kelly R., Cullen M.J., Richards S.J., 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: 567–73. DOI: 10.3324/ haematol.2009.007229

57. Holers V.M. The complement system as a therapeutic target in autoimmunity. Clin Immunol 2003; 107: 140–51. DOI: 10.1016/S1521-6616(03)00034-2

58. Morgan B.P., Harris C.L. Complement, a target for therapy in inflammatory and degenerative diseases. Nature reviews. Drug Discov 2015; 14: 857–77. DOI: 10.1038/nrd4657

59. Sahu A., Kay B.K., Lambris J.D. Inhibition of human complement by a C3-binding peptide isolated from a phage-displayed random peptide library. J Immunol 1996; 157 (2): 884–91.

60. Ricklin D., Lambris J.D. Compstatin: a complement inhibitor on its way to clinical application. Adv Exp Med Biol 2008; 632: 273–92. DOI: 10.1007/978-0-387-78952-1-20

61. Amyndas Pharmaceuticals press release about positive preliminary results from a Phase 1 clinical trial of its C3-targeted complement inhibitor, AMY-101, 2017. Available at: https://www.amyndas.com/amyndas-pharmaceuticals-announces-positive-results-from-a-phase-i-trial-of-its-new-complement-c3-inhibitor-amy-101/

62. Lambris J., Reis E., Berger N., Lang M.H., Nilsson B., Smith R., et al. An update on the clinical development of compstatin (AMY-101). In: 11th International Conference on Complement Therapeutics. Chania 2018: 142.

63. 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 2013; 218: 496–505. DOI: 10.1016/j.imbio.2012.06.003

64. Grossi F.V., Bedwell P., Deschatelets P., Edis L., Francois C.G., Johnson P.J., et al. APL-2, a complement C3 inhibitor for the potential treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH): Phase I data fromtwo completed studies in healthy volunteers. Blood 2016; 128: 1251.

65. A Phase III, Randomized, Multi-Center, Open-Label, Active-Comparator Controlled Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH). ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03500549

66. Morgan B.P., Thanassi J., Podos S., Phadke A., Gadhachanda V., Pais G., et al. Novel small-molecule inhibitors targeting complement factor D for therapy of paroxysmal nocturnal hemoglobinuria. Blood 2014; 124: 4817.

67. Wiles J., Podos S., Thanassi J., Phadke A., Gadhachanda V., Pais G., et al. Preclinical evaluation of orally bioavailable small-molecule inhibitors of complement factor D as a potential treatment for paroxysmal nocturnal hemoglobinuria. Blood 2014; 124: 4819.

68. A Treatment Study of ACH-0144471 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH). ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03053102

69. A Treatment Study of ACH-0144471 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) With Inadequate Response to Eculizumab. ClinicalTrials. gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03472885

70. Maibaum J., Liao S.M., Vulpetti A., Ostermann N., Randl S., Rudisser S., et al. Small-molecule factor D inhibitors targeting the alternative complement pathway. Nat Chem Biol 2016; 12: 1105–10. DOI: 10.1038/nchembio.2208

71. Schubart A., Maibaum J., Anderson K., Sellner H., MacSweeney A., Littlewood-Evans A., et al. Small-molecule factor B inhibitorsfor oral treatment of alternative pathway driven diseases. In: 9th International Conference on Complement Therapeutics. Rhodes; 2016.

72. Study of Safety, Efficacy, Tolerability, Pharmacokinetics and Pharmacodynamics of LNP023 in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03439839