моноклональные антитела

Элотузумаб в лечении множественной миеломы (обзор литературы)

ЛИМФОИДНЫЕ ОПУХОЛИ , , ,

О.М. Вотякова

ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России, Каширское ш., д. 24, Москва, Российская Федерация, 115478

Для переписки: Ольга Михайловна Вотякова, канд. мед. наук, Каширское ш., д. 24, Москва, Российская Федерация, 115478; тел.: +7(499)324-92-09; e-mail: omvtk@yandex.ru

Для цитирования: Вотякова О.М. Элотузумаб в лечении множественной миеломы (обзор литературы). Клиническая онкогематология. 2016;9(4):438–45.

DOI: 10.21320/2500-2139-2016-9-4-438-445

РЕФЕРАТ

Основным методом лечения множественной миеломы на протяжении десятилетий была химиотерапия. Однако значительное увеличение продолжительности жизни больных отмечено после внедрения в клиническую практику талидомида, бортезомиба и леналидомида. Тем не менее болезнь остается неизлечимой и необходима разработка принципиально новых лечебных подходов. Элотузумаб — это гуманизированное моноклональное антитело IgG1, специфической мишенью которого является антиген SLAMF7. Он относится к семейству сигнальных молекул, активирующих лимфоциты. Высокая экспрессия этого антигена выявляется на миеломных клетках. В обзоре представлены механизм действия элотузумаба, доклинические данные и основные клинические исследования.

Ключевые слова: моноклональные антитела, элотузумаб, клинические исследования, множественная миелома.

Получено: 25 мая 2016 г.

Принято в печать: 15 июня 2016 г.

Читать статью в PDFpdficon

ЛИТЕРАТУРА

  1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374–403. doi: 10.1016/j.ejca.2012.12.027.
  2. Статистика злокачественных новообразований в России и странах СНГ в 2012 г. Под ред. М.И. Давыдова, Е.М. Аксель. М.: Издательская группа РОНЦ им. Н.Н. Блохина, 2014. 226 с.
    [Davydova MI, Aksel’ EM, eds. Statistika zlokachestvennykh novoobrazovanii v Rossii i stranakh SNG v 2012 g. (Statistics of malignancies in Russia and CIS in) Moscow: Izdatel’skaya gruppa RONTs im. N.N. Blokhina Publ.; 2014. 226 p. (In Russ)]
  3. EER Stat Fact Sheets: Myeloma, 2004–2010. [Internet] Available from: http://seer.cancer.gov/statfacts/html/mulmy.html. (accessed 25.08.2014).
  4. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20. doi: 10.1182/blood-2007-10-116129.
  5. Madan S, Lacy M, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory compounds in patients receiving initial therapy for newly diagnosed multiple myeloma. Blood. 2010;116(21): Abstract 1964.
  6. Knopf KB, Duh MS, Lafeuille M-H, et al. Meta-Analysis of the Efficacy and Safety of Bortezomib Re-treatment in Patients with Multiple Myeloma. Clin Lymph Myel 14(5):380–8. doi: 10.1016/j.clml.2014.03.005.
  7. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79(7):867–74. doi: 10.4065/79.7.867.
  8. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–57. doi: 10.1038/leu.2011.196.
  9. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, Phase III trial. Lancet Oncol. 2013;14(11):1055–66. doi: 10.1016/S1470-2045(13)70380-2.
  10. Siegel DS, Martin T, Wang M, et al. A Phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapse and refractory multiple myeloma. Blood. 2012;120(14):2817–25. doi: 10.1182/blood-2012-05-425934.
  11. Abdi J, Chen G, Chang H. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms. Oncotarget. 2013;4(12):2186–207. doi: 10.18632/oncotarget.1497.
  12. Palumbo A, Sonneveld P. Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma. Exp Rev Hematol. 2015;8(4):481–91. doi: 10.1586/17474086.2015.1053866.
  13. Pratt G, Goodyear O, Moss P. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol. 2007;138(5):563–79. doi: 10.1111/j.1365-2141.2007.06705.x.
  14. Kellner J, Liu B, Kang Y, Li Z. Fact or fiction–identifying the elusive multiple myeloma stem cell. J Hematol Oncol. 2013;7(6):91. doi: 10.1186/1756-8722-6-91.
  15. Stewart AK, Rajkumar SV, Dimopoulos MA, et al.; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52. doi: 10.1056/NEJMoa1411321.
  16. Mentlik JA, Cohen AD, Campbell KS. Combination immune therapies to enhance anti-tumor responses by NK cells. Front Immunol. 2013;23(4):481. doi: 10.3389/fimmu.2013.00481.
  17. Rossi M, Botta C, Correale P, et al. Immunologic microenvironment and personalized treatment in multiple myeloma. Expert Opin Biol Ther. 2013;13(Suppl 1):S83–93. doi: 10.1517/14712598.2013.799130.
  18. Palumbo A, Cavallo F. Have drug combinations supplanted stem cell transplantation in myeloma? Blood. 2012;120(24):4692–8. doi: 10.1182/blood-2012-05-423202.
  19. Teh BW, Harrison SJ, Pellegrini M, et al. Changing treatment paradigms for patients with plasma cell myeloma: impact upon immune determinants of infection. Blood Rev. 2014;28(2):75–86. doi: 10.1016/j.blre.2014.01.004.
  20. Feyler S, Selby PJ, Cook G. Regulating the regulators in cancer-immunosuppression in multiple myeloma (MM). Blood Rev. 2013;27(3):155–64. doi: 10.1016/j.blre.2013.04.004.
  21. Yi Q. Novel immunotherapies. Cancer J. 2009;15(6):502–10. doi: 10.1097/PPO.0b013e3181c51f0d.
  22. Lonial S, Kaufman J, Laubach J, Richardson P. Elotuzumab: a novel anti-CS1 monoclonal antibody for the treatment of multiple myeloma. Expert Opin Biol Ther. 2013;13(12):1731–40. doi: 10.1517/14712598.2013.847919.
  23. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14(9):2775–84. doi: 10.1158/1078-0432.CCR-07-4246.
  24. Veillette A. SLAM-family receptors: immune regulators with or without SAP-family adaptors. Cold Spring Harb Perspect Biol. 2010;2(3):a002469. doi: 10.1101/cshperspect.a002469.
  25. Bouchon A, Cella M, Grierson HL, et al. Cutting edge: activation of NK cell-mediated cytotoxicity by a SAP-independent receptor of the CD2 family. J Immunol. 2001;167(10):5517–21. doi: 10.4049/jimmunol.167.10.5517.
  26. Cruz-Munoz ME, Dong Z, Shi X, et al. Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function. Nat Immunol. 2009;10(3):297–305. doi: 10.1038/ni.1693.
  27. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62(12):1841–9. doi: 10.1007/s00262-013-1493-8.
  28. Tai YT, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood. 2008;112(4):1329–37. doi: 10.1182/blood-2007-08-107292.
  29. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol Hematol. 2013;88(1):168–77. doi: 10.1016/j.critrevonc.2013.04.003.
  30. Moreau Ph, Touzeau K. Elotuzubab for the treatment multiple myeloma. Fut Oncol. 2014;10(6):949–56. doi: 10.2217/fon.14.56.
  31. Benson DM. Jr, Byrd JC. CS1-directed monoclonal antibody therapy for multiple myeloma. J Clin Oncol. 2012;30(16):2013–5. doi: 10.1200/jco.2011.40.4061.
  32. Balasa B, Yun R, Belmar NA, et al. Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-a Cancer Immunol Immunother. 2015;64(1):61–73. doi: 10.1007/s00262-014-1610-3.
  33. van Rhee F, Szmania SM, Dillon M, et al. Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma. Mol Cancer Ther. 2009;8(9):2616–24. doi: 10.1158/1535-7163.MCT-09-0483.
  34. Zonder JA, Mohrbacher AF, Singhal S, et al. A Phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120(3):552–9. doi: 10.1182/blood-2011-06-360552.
  35. Jakubowiak AJ, Benson DM, Bensinger W, et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol. 2012;30(16):1960–5. doi: 10.1200/jco.2011.37.7069.
  36. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30(16):1953–9. doi: 10.1200/jco.2011.37.2649.
  37. Eleutherakis-Papaiakovou V, Bamias A, Gika D, et al. Renal failure in multiple myeloma: incidence, correlations, and prognostic significance. Leuk Lymphoma. 2007;48(2):337–41. doi: 10.1080/10428190601126602.
  38. Berdeja J, Jagannath S, Zonder J, et al. Pharmacokinetics and Safety of Elotuzumab Combined With Lenalidomide and Dexamethasone in Patients With Multiple Myeloma and Various Levels of Renal Impairment: Results of a Phase Ib Study. Clin Lymph Myel Leuk. 2016;16(3):129–38. doi: 1016/j.clml.2015.12.007.
  39. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, Refractory myeloma. N Engl J Med. 2003;348(26):2609–17. doi: 1056/nejmoa030288.
  40. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–98. doi: 10.1056/nejmoa043445.
  41. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. 2009;23(11):2147–52. doi: 10.1038/leu.2009.147.
  42. Jakubowiak A, Offidani M, Pegourie B, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. 2016;127(23):2833–40. doi: 10.1182/blood-2016-01-694604.
  43. Richardson PG, Jagannath S, Moreau P, et al. Final results for the 1703 phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. 2014;124(21): Abstract 302.
  44. Phase III Study of Lenalidomide and Dexamethasone With or Without Elotuzumab to Treat Newly Diagnosed, Previously Untreated Multiple Myeloma (ELOQUENT-1). [Internet] Available from: clinicaltrials.gow/ct2/show/NCT01335399. (accessed 21.05.2016).
  45. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373(7):621–31. doi: 10.1056/NEJMoa1505654.
  46. Lonial S, Dimopoulos M, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;33(Suppl): Abstract 8508.
  47. Genzen JR, Kawaguchi KR, Furman RR. Detection of a monoclonal antibody therapy (ofatumumab) by serum protein and immunofixation electrophoresis. Br J Haematol. 2011;155(1):123–5. doi: 10.1111/j.1365-2141.2011.08644.x.
  48. McCudden CR, Voorhees PM, Hainsworth SA, et al. Interference of monoclonal antibody therapies with serum protein electrophoresis tests. Clin Chem. 2010;56(12):1897–9. doi: 10.1373/clinchem.2010.152116.
  49. Axel AE, McCudden CR, Xie H, et al. Development of clinical assay to mitigate daratumumab, an IgG1K monoclonal antibody, interference with serum immunofixation (IFE) and clinical assessment of M-protein response in multiple myeloma. Cancer Res. 2014;74(19):2563. doi: 10.1158/1538-7445.am2014-2563.
  50. US Food and Drug Administration. Elotuzumab [media release]. [Internet] Available from: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm474719.htm. (accessed 22.05.2016).
  51. European commission Community register of medicinal products for human usе. [Internet] Available from: http://ec.europa.eu/health/documents/community-register/html/h1088.htm. (accessed 22.05.2016).
  52. NCCN Clinical Guidelines Version 3.2016. [Internet] Available from: https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. (accessed 23.05.2016).

 

Моноклональные антитела: от создания до клинического применения

ОБЗОРЫ , , , ,

Ю.И. Будчанов

ГБОУ ВПО «Тверской медицинский университет», ул. Советская, д. 4, Тверь, Российская Федерация, 170000

Для переписки: Юрий Иванович Будчанов, 1-й пер. Красной Слободы, д. 3, Тверь, Российская Федерация, 170001; e-mail: budjur@mail.ru

Для цитирования: Будчанов Ю.И. Моноклональные антитела: от создания до клинического применения. Клиническая онкогематология. 2016;9(3):237-44.

DOI: 10.21320/2500-2139-2016-9-3-237-244

РЕФЕРАТ

Создание моноклональных антител (МКА) привело к революционным достижениям в диагностике и лечении онкогематологических заболеваний. В обзоре рассматриваются история создания, новые улучшенные технологии получения моноклональных антител на примере анти-CD20-МКА, распознающих различные эпитопы антигена CD20 и обладающих повышенной противоопухолевой активностью. Инженерные модификации должны помочь понять эффекторные механизмы использования новых анти-CD20-МКА и направлены на дальнейшее улучшение результатов лечения.

Ключевые слова: моноклональные антитела, ритуксимаб, офатумумаб, обинутузумаб, гибридомная технология.

Получено: 13 января 2016 г.

Принято в печать: 17 марта 2016 г.

Читать статью в PDFpdficon

ЛИТЕРАТУРА

  1. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256(5517):495–7. doi: 10.1038/256495a0.
  2. Galfre G. Antibodies to major histocompatibility antigens produced by hybrid cell lines. Nature. 1977;266(5602):550–2. doi: 10.1038/266550a0.
  3. Гордеева О.Б., Семикина Е.Л. Современные возможности определения группы крови и резус-принадлежности в педиатрической практике. Вопросы диагностики в педиатрии. 2010;2(4):9–16.
    [Gordeeva OB, Semikina EL. Current capabilities of the blood group and Rhesus factor typing in pediatric practice. Voprosy diagnostiki v pediatrii. 2010;2(4):9–16. (In Russ)]
  4. Рагимов А.А., Дашкова Н.Г. Трансфузионная иммунология. М.: МИА, 2004. С. 270.
    [Ragimov AA, Dashkova NG. Transfuzionnaya immunologiya. (Transfusion immunology.) Moscow: MIA Publ.; 2004. pp. 270. (In Russ)]
  5. Freedman A. Follicular lymphoma: 2014 update on diagnosis and management. Am J Hematol. 2014;89(4):429–36. doi: 10.1002/ajh.23674.
  6. Preijers FW, Huys E, Moshaver B. OMIP-010: a new 10-color monoclonal antibody panel for polychromatic immunophenotyping of small hematopoietic cell samples. Cytometry A. 2012;81A(6):453–5. doi: 10.1002/cyto.a.22056.
  7. Тупицын Н.Н., Гривцова Л.Ю., Купрышина Н.А. Иммунодиагностика опухолей крови на основании многоцветных (8 цветов панелей) европейского консорциума по проточной цитометрии (EURO-FLOW). Иммунология гемопоэза. 2015;13(1):31–62.
    [Tupitsyn NN, Grivtsova LYu, Kupryshina NA. Haematopoietic malignancies immune diagnostics based on Euroflow Consortium proposals: 8-color flow cytometry. Immunologiya gemopoeza. 2015;13(1):31–62. (In Russ)]
  8. Тупицын Н.Н. Иммунология клеток крови. В кн.: Гематология. Национальное руководство. Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. С. 69–79.
    [Tupitsyn NN. Blood cell immunology. In: Rukavitsyn OA, ed. Gematologiya. Natsional’noe rukovodstvo. (Hematology. National guidelines.) Moscow: GEOTAR-Media Publ.; 2015. pp. 69–79. (In Russ)]
  9. Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol. 2006;6:343–57. doi: 10.1038/nri1837.
  10. Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol. 2000;27(12):17–24.
  11. Tedder TF, Engel P. CD20: a regulator of cell-cycle progression of B lymphocytes. Immunol Today. 1994;15(9):450–4. doi: 10.1016/0167-5699(94)90276-3.
  12. Renaudineau Y, Devauchelle-Pensec V, Hanrotel C, et al. Monoclonal anti-CD20 antibodies: mechanisms of action and monitoring of biological effects. Joint Bone Spine. 2009;76(5):458–63. doi: 10.1016/j.jbspin.2009.03.010.
  13. Martin P, Furman RR, Coleman M, Leonard JP. Phase I to III trials of anti-B cell therapy in non-Hodgkin’s lymphoma. Clin Cancer Res. 2007;13(18):5636–42. doi: 10.1158/1078-0432.ccr-07-1085.
  14. St Clair EW. Novel targeted therapies for autoimmunity. Curr Opin Immunol. 2009;21(6):648–57. doi: 10.1016/j.coi.2009.09.008.
  15. Gurcan H, Keskin D, Stern J, et al. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol. 2009;9(1):10–25. doi: 10.1016/j.intimp.2008.10.004.
  16. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013;8(7):e66308. doi: 10.1371/journal.pone.0066308.
  17. Otukesh H, Hoseini R, Rahimzadeh N, Fazel M. Rituximab in the treatment of nephrotic syndrome: a systematic review. Iran J Kidney Dis. 2013;7(4):249–56. doi: 10.13172/2053-0293-1-1-480.
  18. Morrison VA. Immunosuppression associated with novel chemotherapy agents and monoclonal antibodies. Clin Infect Dis. 2014;59(5):360–4. doi: 10.1093/cid/ciu592.
  19. Rosman Z, Shoenfeld Y, Zandman-Goddard G. Biologic therapy for autoimmune diseases: an update. BMC Med. 2013;11(1):88. doi: 10.1186/1741-7015-11-88.
  20. Bhandari PR, Pai VV. Novel applications of Rituximab in dermatological disorders. Indian Dermatol Online J. 2014;5(3):250–9. doi: 10.4103/2229-5178.137766.
  21. Cang S, Mukhi N, Wang K, Liu D. Novel CD20 monoclonal antibodies for lymphoma therapy. J Hematol Oncol. 2012;5(1):64. doi: 10.1186/1756-8722-5-64.
  22. Rioufol C, Salles G. Obinutuzumab for chronic lymphocytic leukemia. Expert Rev Hematol. 2014;7(5):533–43. doi: 10.1586/17474086.2014.953478.
  23. Owen CJ, Stewart DA. Obinutuzumab for the treatment of patients with previously untreated chronic lymphocytic leukemia: overview and perspective. Ther Adv Hematol. 2015;6(4):161–70. doi: 10.1177/2040620715586528.
  24. Shah A. Obinutuzumab: A Novel Anti-CD20 Monoclonal Antibody for Previously Untreated Chronic Lymphocytic Leukemia. Ann Pharmacother. 2014;48(10):1356–61. doi: 10.1177/1060028014543271.
  25. Golay J, Da Roit F, Bologna L, et al. Glycoengineered CD20 antibody obinutuzumab activates neutrophils and mediates phagocytosis through CD16B more efficiently than rituximab. Blood. 2013;122(20):3482–91. doi: 10.1182/blood-2013-05-504043.
  26. Shah A. New developments in the treatment of chronic lymphocytic leukemia: role of obinutuzumab. Ther Clin Risk Manage. 2015;11:1113–22. doi: 10.2147/TCRM.S71839.
  27. Cerquozzi S, Owen C. Clinical role of obinutuzumab in the treatment of naive patients with chronic lymphocytic leukemia. Biol Targ Ther. 2015;9:13–22. doi: 10.2147/BTT.S61600.
  28. Seiter K, Mamorska-Dyga A. Obinutuzumab treatment in the elderly patient with chronic lymphocytic leukemia. Clin Interv Aging. 2015;12(10):951–61. doi: 10.2147/cia.s69278.
  29. Алексеев С.М., Капланов К.Д., Иванов Р.А., Черняева Е.В. Современный подход к разработке и исследованию биоаналогов на примере первого российского препарата моноклональных антител — Ацеллбия® (ритуксимаб). Исследования и практика в медицине. 2015;2(1):8–12. doi: 10.17709/2409-2231-2015-2-1-8-12.
    [Alekseev SM, Kaplanov KD, Ivanov RA, Chernyaeva EV. Current approach to development of biosimilar products containing monoclonal antibodies as an active substance – non-clinical studies of the first Russian rituximab biosimilar, Acellbia®. Research’n Practical Medicine Journal. 2015;2(1):8–12. doi: 10.17709/2409-2231-2015-2-1-8-12. (In Russ)]
  30. Tada M, Tatematsu K-I, Ishii-Watabe A, et al. Characterization of anti-CD20 monoclonal antibody produced by transgenic silkworms (Bombyx mori). mAbs. 2015;7(6):1138–50. doi: 10.1080/19420862.2015.1078054.
  31. Gonzalez-Gonzalez E, Alvarez MM, Marquez-Ipina AR, et al. Anti-Ebola therapies based on monoclonal antibodies: current state and challenges ahead. Crit Rev Biotechnol. 2015;26:1–16. doi: 10.3109/07388551.2015.1114465.