Systematic Review of Safety and Efficacy of Second- and Third-Generation CD20-Targeting Biologics in Treating Immune-Mediated Disorders
Journal: 2022/February - Frontiers in Immunology
Abstract:
Background: B cells can contribute to immune-mediated disorders. Targeting CD20 has proved to be efficacious in several B cell-mediated immunopathologies, as illustrated by the use of rituximab, the first anti-CD20 monoclonal antibody (mAb). Following rituximab, second- and third-generation anti-CD20 mAbs have been developed and tried in immune-mediated diseases, including obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab. However, their safety and efficacy has not been systematically reviewed.
Objective: To evaluate safety and efficacy of obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics.
Methods: The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 22 July 2021 concentrating on immune-mediated disorders.
Results: The literature search identified 2220 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 27 articles were finally included in a narrative synthesis.
Conclusions: Obinutuzumab has shown promising results in a case series of patients with phospholipase A2 receptor-associated membranous nephropathy and mixed results in systemic lupus erythematosus. Ocrelizumab has been approved for the use in patients with relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. Ocrelizumab was also tested in patients with rheumatoid arthritis, demonstrating promising results, and in systemic lupus erythematosus, revealing mixed results; however, in these conditions, its use was associated with increased risk of serious infections. Ofatumumab received approval for treating patients with relapsing-remitting multiple sclerosis. Moreover, ofatumumab showed promising results in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, rheumatoid arthritis, and systemic lupus erythematosus, as well as mixed results in phospholipase A2 receptor-associated membranous nephropathy. Ublituximab was assessed in relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorder, with promising results, however, the included number of patients was too small to conclude. Veltuzumab was tested in patients with immune thrombocytopenia resulting in improved platelet counts.
Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD4201913421.
Keywords: immune-mediated diseases; multiple sclerosis; obinutuzumab; ocrelizumab; ofatumumab; systemic lupus erythematosus; ublituximab; veltzumab.
Relations:
Content
References
(52)
Diseases
(6)
Conditions
(1)
Chemicals
(5)
Anatomy
(3)
Similar articles
Articles by the same authors
Discussion board

Systematic Review of Safety and Efficacy of Second- and Third-Generation CD20-Targeting Biologics in Treating Immune-Mediated Disorders

Click here for additional data file.(17K, docx)
Click here for additional data file.(83K, docx)
Department of Immunology, University Hospital Zurich, Zurich, Switzerland,
Faculty of Medicine, University of Zurich, Zurich, Switzerland,
Corresponding author.
Edited by: Ioannis Parodis, Karolinska Institutet (KI), Sweden
Reviewed by: Harry Alexopoulos, National and Kapodistrian University of Athens, Greece; Venkat Reddy, University College London, United Kingdom
*Correspondence: Onur Boyman, hc.hzu@namyob.runo
This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology
Edited by: Ioannis Parodis, Karolinska Institutet (KI), Sweden
Reviewed by: Harry Alexopoulos, National and Kapodistrian University of Athens, Greece; Venkat Reddy, University College London, United Kingdom
Received 2021 Oct 3; Accepted 2021 Dec 17.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Background

B cells can contribute to immune-mediated disorders. Targeting CD20 has proved to be efficacious in several B cell-mediated immunopathologies, as illustrated by the use of rituximab, the first anti-CD20 monoclonal antibody (mAb). Following rituximab, second- and third-generation anti-CD20 mAbs have been developed and tried in immune-mediated diseases, including obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab. However, their safety and efficacy has not been systematically reviewed.

Objective

To evaluate safety and efficacy of obinutuzumab, ocrelizumab, ofatumumab, ublituximab, and veltuzumab for the treatment of immune-mediated disorders compared to placebo, conventional treatment or other biologics.

Methods

The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 4 October 2016 and 22 July 2021 concentrating on immune-mediated disorders.

Results

The literature search identified 2220 articles. After screening titles and abstracts against the inclusion and exclusion criteria and assessing full texts, 27 articles were finally included in a narrative synthesis.

Conclusions

Obinutuzumab has shown promising results in a case series of patients with phospholipase A2 receptor-associated membranous nephropathy and mixed results in systemic lupus erythematosus. Ocrelizumab has been approved for the use in patients with relapsing-remitting multiple sclerosis and primary progressive multiple sclerosis. Ocrelizumab was also tested in patients with rheumatoid arthritis, demonstrating promising results, and in systemic lupus erythematosus, revealing mixed results; however, in these conditions, its use was associated with increased risk of serious infections. Ofatumumab received approval for treating patients with relapsing-remitting multiple sclerosis. Moreover, ofatumumab showed promising results in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, rheumatoid arthritis, and systemic lupus erythematosus, as well as mixed results in phospholipase A2 receptor-associated membranous nephropathy. Ublituximab was assessed in relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorder, with promising results, however, the included number of patients was too small to conclude. Veltuzumab was tested in patients with immune thrombocytopenia resulting in improved platelet counts.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/, identifier CRD4201913421.

Keywords: obinutuzumab, ocrelizumab, ofatumumab, ublituximab, veltzumab, immune-mediated diseases, systemic lupus erythematosus, multiple sclerosis
Abstract

Level I  Approved by the EMA and/or FDA.

Level IIa  Multicentric double-blind RCTs proving a significant superiority over standard-of-care treatment.

Level IIb  Multicentric double-blind RCTs proving a significant superiority over placebo.

Level IIIa Clinical study, not fulfilling the above-mentioned criteria, but proving a superiority over standard-of-care treatment.

Level IIIb Clinical study, not fulfilling the above-mentioned criteria, but proving a superiority over placebo.

Level IV  Case series or open-label trials without control group with positive results.

An external file that holds a picture, illustration, etc.
Object name is fimmu-12-788830-i001.jpg Achieved

An external file that holds a picture, illustration, etc.
Object name is fimmu-12-788830-i002.jpg Failed

An external file that holds a picture, illustration, etc.
Object name is fimmu-12-788830-i003.jpg Mixed result

*Increased risk of serious infections.

AAV, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; ITP, immune thrombocytopenia; MS, multiple sclerosis; PLA2R-MN, phospholipase A2 receptor-associated membranous nephropathy; RA, rheumatoid arthritis; RCT, randomized controlled trial; SLE, systemic lupus erythematosus.

Click here for additional data file.(17K, docx)Click here for additional data file.(83K, docx)

References

  • 1. Fugger L, Jensen LT, Rossjohn J. Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases. Cell (2020) 181:63–80. doi: 10.1016/j.cell.2020.03.007 [] [[PubMed]
  • 2. Jelcic I, Al Nimer F, Wang J, Lentsch V, Planas R, Jelcic I, et al. . Memory B Cells Activate Brain-Homing, Autoreactive CD4(+) T Cells in Multiple Sclerosis. Cell (2018) 175:85–100.e123. doi: 10.1016/j.cell.2018.08.011 ] [
  • 3. Cain DW, Cidlowski JA. Immune Regulation by Glucocorticoids. Nat Rev Immunol (2017) 17:233–47. doi: 10.1038/nri.2017.1 [] [[PubMed]
  • 4. Ulrich C, Kanitakis J, Stockfleth E, Euvrard S. Skin Cancer in Organ Transplant Recipients–Where Do We Stand Today? Am J Transplant (2008) 8:2192–8. doi: 10.1111/j.1600-6143.2008.02386.x [] [[PubMed]
  • 5. Boyman O, Kaegi C, Akdis M, Bavbek S, Bossios A, Chatzipetrou A, et al. . EAACI IG Biologicals Task Force Paper on the Use of Biologic Agents in Allergic Disorders. Allergy (2015) 70:727–54. doi: 10.1111/all.12616 [] [[PubMed]
  • 6. Boyman O, Comte D, Spertini F. Adverse Reactions to Biologic Agents and Their Medical Management. Nat Rev Rheumatol (2014) 10:612–27. doi: 10.1038/nrrheum.2014.123 [] [[PubMed]
  • 7. Kaegi C, Wuest B, Schreiner J, Steiner UC, Vultaggio A, Matucci A, et al. . Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders. Front Immunol (2019) 10:1990. doi: 10.3389/fimmu.2019.01990 ] [
  • 8. Kaegi C, Steiner UC, Wuest B, Crowley C, Boyman O. Systematic Review of Safety and Efficacy of Atacicept in Treating Immune-Mediated Disorders. Front Immunol (2020) 11:433. doi: 10.3389/fimmu.2020.00433 ] [
  • 9. Kaegi C, Steiner UC, Wuest B, Crowley C, Boyman O. Systematic Review of Safety and Efficacy of Belimumab in Treating Immune-Mediated Disorders. Allergy (2021) 76:2673–83. doi: 10.1111/all.14704 [] [[PubMed]
  • 10. Pieper K, Grimbacher B, Eibel H. B-Cell Biology and Development. J Allergy Clin Immunol (2013) 131:959–71. doi: 10.1016/j.jaci.2013.01.046 [] [[PubMed]
  • 11. Shen P, Fillatreau S. Antibody-Independent Functions of B Cells: A Focus on Cytokines. Nat Rev Immunol (2015) 15:441–51. doi: 10.1038/nri3857 [] [[PubMed]
  • 12. Marshall MJE, Stopforth RJ, Cragg MS. Therapeutic Antibodies: What Have We Learnt From Targeting CD20 and Where Are We Going? Front Immunol (2017) 8:1245. doi: 10.3389/fimmu.2017.01245 ] [
  • 13. Rouge L, Chiang N, Steffek M, Kugel C, Croll TI, Tam C, et al. . Structure of CD20 in Complex With the Therapeutic Monoclonal Antibody Rituximab. Science (2020) 367:1224–30. doi: 10.1126/science.aaz9356 [] [[PubMed]
  • 14. Townsend MJ, Monroe JG, Chan AC. B-Cell Targeted Therapies in Human Autoimmune Diseases: An Updated Perspective. Immunol Rev (2010) 237:264–83. doi: 10.1111/j.1600-065X.2010.00945.x [] [[PubMed]
  • 15. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. . Efficacy of B-Cell-Targeted Therapy With Rituximab in Patients With Rheumatoid Arthritis. N Engl J Med (2004) 350:2572–81. doi: 10.1056/NEJMoa032534 [] [[PubMed]
  • 16. Hamza N, Bootsma H, Yuvaraj S, Spijkervet FK, Haacke EA, Pollard RP, et al. . Persistence of Immunoglobulin-Producing Cells in Parotid Salivary Glands of Patients With Primary Sjogren's Syndrome After B Cell Depletion Therapy. Ann Rheum Dis (2012) 71:1881–7. doi: 10.1136/annrheumdis-2011-201189 [] [[PubMed]
  • 17. Reddy V, Martinez L, Isenberg DA, Leandro MJ, Cambridge G. Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long-Term Effects on Serum Immunoglobulins. Arthritis Care Res (Hoboken) (2017) 69:857–66. doi: 10.1002/acr.22993 ] [
  • 18. Walshe CA, Beers SA, French RR, Chan CH, Johnson PW, Packham GK, et al. . Induction of Cytosolic Calcium Flux by CD20 Is Dependent Upon B Cell Antigen Receptor Signaling. J Biol Chem (2008) 283:16971–84. doi: 10.1074/jbc.M708459200 [] [[PubMed]
  • 19. Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, et al. . Increasing the Efficacy of CD20 Antibody Therapy Through the Engineering of a New Type II Anti-CD20 Antibody With Enhanced Direct and Immune Effector Cell-Mediated B-Cell Cytotoxicity. Blood (2010) 115:4393–402. doi: 10.1182/blood-2009-06-225979 ] [
  • 20. Reddy V, Dahal LN, Cragg MS, Leandro M. Optimising B-Cell Depletion in Autoimmune Disease: Is Obinutuzumab the Answer? Drug Discov Today (2016) 21:1330–8. doi: 10.1016/j.drudis.2016.06.009 [] [[PubMed]
  • 21. Reddy V, Klein C, Isenberg DA, Glennie MJ, Cambridge G, Cragg MS, et al. . Obinutuzumab Induces Superior B-Cell Cytotoxicity to Rituximab in Rheumatoid Arthritis and Systemic Lupus Erythematosus Patient Samples. Rheumatology (Oxford) (2017) 56:1227–37. doi: 10.1093/rheumatology/kex067 ] [
  • 22. Tobinai K, Klein C, Oya N, Fingerle-Rowson G. A Review of Obinutuzumab (GA101), A Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients With B-Cell Malignancies. Adv Ther (2017) 34:324–56. doi: 10.1007/s12325-016-0451-1 ] [
  • 23. Kumar A, Planchais C, Fronzes R, Mouquet H, Reyes N. Binding Mechanisms of Therapeutic Antibodies to Human CD20. Science (2020) 369:793–9. doi: 10.1126/science.abb8008 [] [[PubMed]
  • 24. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. BMJ (2009) 339:b2535.
  • 25. Downs SH, Black N. The Feasibility of Creating a Checklist for the Assessment of the Methodological Quality Both of Randomised and non-Randomised Studies of Health Care Interventions. J Epidemiol Community Health (1998) 52:377–84. doi: 10.1136/jech.52.6.377 ] [
  • 26. Klomjit N, Fervenza FC, Zand L. Successful Treatment of Patients With Refractory PLA2R-Associated Membranous Nephropathy With Obinutuzumab: A Report of 3 Cases. Am J Kidney Dis (2020) 76:883–8. doi: 10.1053/j.ajkd.2020.02.444 [] [[PubMed]
  • 27. Furie RA, Aroca G, Cascino MD, Garg JP, Rovin BH, Alvarez A, et al. . B-Cell Depletion With Obinutuzumab for the Treatment of Proliferative Lupus Nephritis: A Randomised, Double-Blind, Placebo-Controlled Trial. Ann Rheum Dis (2021) 2021-220920. doi: 10.1136/annrheumdis-2021-220920 ] [
  • 28. Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, et al. . Ocrelizumab in Relapsing-Remitting Multiple Sclerosis: A Phase 2, Randomised, Placebo-Controlled, Multicentre Trial. Lancet (2011) 378:1779–87. doi: 10.1016/S0140-6736(11)61649-8 [] [[PubMed]
  • 29. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. . Ocrelizumab Versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med (2017) 376:221–34. doi: 10.1056/NEJMoa1601277 [] [[PubMed]
  • 30. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. . Ocrelizumab Versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med (2017) 376:209–20. doi: 10.1056/NEJMoa1606468 [] [[PubMed]
  • 31. Hartung HP, Berger T, Bermel RA, Brochet B, Carroll WM, Holmoy T, et al. . Shorter Infusion Time of Ocrelizumab: Results From the Randomized, Double-Blind ENSEMBLE PLUS Substudy in Patients With Relapsing-Remitting Multiple Sclerosis. Mult Scler Relat Disord (2020) 46:102492. doi: 10.1016/j.msard.2020.102492 ] [
  • 32. Hauser SL, Kappos L, Arnold DL, Bar-Or A, Brochet B, Naismith RT, et al. . Five Years of Ocrelizumab in Relapsing Multiple Sclerosis: OPERA Studies Open-Label Extension. Neurology (2020) 95:e1854–67. doi: 10.1212/WNL.0000000000010376 ] [
  • 33. Genovese MC, Kaine JL, Lowenstein MB, Del Giudice J, Baldassare A, Schechtman J, et al. . Ocrelizumab, a Humanized Anti-CD20 Monoclonal Antibody, in the Treatment of Patients With Rheumatoid Arthritis: A Phase I/II Randomized, Blinded, Placebo-Controlled, Dose-Ranging Study. Arthritis Rheum (2008) 58:2652–61. doi: 10.1002/art.23732 [] [[PubMed]
  • 34. Harigai M, Tanaka Y, Maisawa S, Group, J.A.S . Safety and Efficacy of Various Dosages of Ocrelizumab in Japanese Patients With Rheumatoid Arthritis With an Inadequate Response to Methotrexate Therapy: A Placebo-Controlled Double-Blind Parallel-Group Study. J Rheumatol (2012) 39:486–95. doi: 10.3899/jrheum.110994 [] [[PubMed]
  • 35. Rigby W, Tony HP, Oelke K, Combe B, Laster A, von Muhlen CA, et al. . Safety and Efficacy of Ocrelizumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Forty-Eight-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase III Trial. Arthritis Rheum (2012) 64:350–9. doi: 10.1002/art.33317 [] [[PubMed]
  • 36. Stohl W, Gomez-Reino J, Olech E, Dudler J, Fleischmann RM, Zerbini CA, et al. . Safety and Efficacy of Ocrelizumab in Combination With Methotrexate in MTX-Naive Subjects With Rheumatoid Arthritis: The Phase III FILM Trial. Ann Rheum Dis (2012) 71:1289–96. doi: 10.1136/annrheumdis-2011-200706 ] [
  • 37. Tak PP, Mease PJ, Genovese MC, Kremer J, Haraoui B, Tanaka Y, et al. . Safety and Efficacy of Ocrelizumab in Patients With Rheumatoid Arthritis and an Inadequate Response to at Least One Tumor Necrosis Factor Inhibitor: Results of a Forty-Eight-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase III Trial. Arthritis Rheum (2012) 64:360–70. doi: 10.1002/art.33353 [] [[PubMed]
  • 38. Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, et al. . Efficacy and Safety of Ocrelizumab in Active Proliferative Lupus Nephritis: Results From a Randomized, Double-Blind, Phase III Study. Arthritis Rheum (2013) 65:2368–79. doi: 10.1002/art.38037 [] [[PubMed]
  • 39. McAdoo SP, Bedi R, Tarzi R, Griffith M, Pusey CD, Cairns TD. Ofatumumab for B Cell Depletion Therapy in ANCA-Associated Vasculitis: A Single-Centre Case Series. Rheumatology (Oxford) (2016) 55:1437–42. doi: 10.1093/rheumatology/kew199 ] [
  • 40. Podesta MA, Gennarini A, Portalupi V, Rota S, Alessio MG, Remuzzi G, et al. . Accelerating the Depletion of Circulating Anti-Phospholipase A2 Receptor Antibodies in Patients With Severe Membranous Nephropathy: Preliminary Findings With Double Filtration Plasmapheresis and Ofatumumab. Nephron (2020) 144:30–5. doi: 10.1159/000501858 [] [[PubMed]
  • 41. Sorensen PS, Lisby S, Grove R, Derosier F, Shackelford S, Havrdova E, et al. . Safety and Efficacy of Ofatumumab in Relapsing-Remitting Multiple Sclerosis: A Phase 2 Study. Neurology (2014) 82:573–81. doi: 10.1212/WNL.0000000000000125 [] [[PubMed]
  • 42. Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, Lewis EW, et al. . Subcutaneous Ofatumumab in Patients With Relapsing-Remitting Multiple Sclerosis: The MIRROR Study. Neurology (2018) 90:e1805–14. doi: 10.1212/WNL.0000000000005516 ] [
  • 43. Hauser SL, Bar-Or A, Cohen JA, Comi G, Correale J, Coyle PK, et al. . Ofatumumab Versus Teriflunomide in Multiple Sclerosis. N Engl J Med (2020) 383:546–57. doi: 10.1056/NEJMoa1917246 [] [[PubMed]
  • 44. Kurrasch R, Brown JC, Chu M, Craigen J, Overend P, Patel B, et al. . Subcutaneously Administered Ofatumumab in Rheumatoid Arthritis: A Phase I/II Study of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics. J Rheumatol (2013) 40:1089–96. doi: 10.3899/jrheum.121118 [] [[PubMed]
  • 45. Ostergaard M, Baslund B, Rigby W, Rojkovich B, Jorgensen C, Dawes PT, et al. . Ofatumumab, a Human Anti-CD20 Monoclonal Antibody, for Treatment of Rheumatoid Arthritis With an Inadequate Response to One or More Disease-Modifying Antirheumatic Drugs: Results of a Randomized, Double-Blind, Placebo-Controlled, Phase I/II Study. Arthritis Rheum (2010) 62:2227–38. doi: 10.1002/art.27524 [] [[PubMed]
  • 46. Quattrocchi E, Ostergaard M, Taylor PC, van Vollenhoven RF, Chu M, Mallett S, et al. . Safety of Repeated Open-Label Treatment Courses of Intravenous Ofatumumab, A Human Anti-CD20 Monoclonal Antibody, in Rheumatoid Arthritis: Results From Three Clinical Trials. PloS One (2016) 11:e0157961. doi: 10.1371/journal.pone.0157961 ] [
  • 47. Taylor PC, Quattrocchi E, Mallett S, Kurrasch R, Petersen J, Chang DJ. Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody, in Biological-Naive, Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate: A Randomised, Double-Blind, Placebo-Controlled Clinical Trial. Ann Rheum Dis (2011) 70:2119–25. doi: 10.1136/ard.2011.151522 ] [
  • 48. Haarhaus ML, Svenungsson E, Gunnarsson I. Ofatumumab Treatment in Lupus Nephritis Patients. Clin Kidney J (2016) 9:552–5. doi: 10.1093/ckj/sfw022 ] [
  • 49. Fox E, Lovett-Racke AE, Gormley M, Liu Y, Petracca M, Cocozza S, et al. . A Phase 2 Multicenter Study of Ublituximab, a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Patients With Relapsing Forms of Multiple Sclerosis. Mult Scler (2021) 27:420–9. doi: 10.1177/1352458520918375 ] [
  • 50. Mealy MA, Levy M. A Pilot Safety Study of Ublituximab, a Monoclonal Antibody Against CD20, in Acute Relapses of Neuromyelitis Optica Spectrum Disorder. Med (Baltimore) (2019) 98:e15944. doi: 10.1097/MD.0000000000015944 ] [
  • 51. Liebman HA, Saleh MN, Bussel JB, Negrea OG, Horne H, Wegener WA, et al. . Low-Dose Anti-CD20 Veltuzumab Given Intravenously or Subcutaneously Is Active in Relapsed Immune Thrombocytopenia: A Phase I Study. Br J Haematol (2013) 162:693–701. doi: 10.1111/bjh.12448 [] [[PubMed]
  • 52. Liebman HA, Saleh MN, Bussel JB, Negrea OG, Horne H, Wegener WA, et al. . Comparison of Two Dosing Schedules for Subcutaneous Injections of Low-Dose Anti-CD20 Veltuzumab in Relapsed Immune Thrombocytopenia. Haematologica (2016) 101:1327–32. doi: 10.3324/haematol.2016.146738 ] [
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.