Терапия пациентов с нейробластомой группы высокого риска с использованием гуманизированного моноклонального антитела

Несмотря на применение мультимодальной терапии у пациентов с нейробластомой (НБ) группы высокого риска, прогноз у них остается неблагоприятным. Иммунотерапия моноклональными антителами (мАТ) в постконсолидационном периоде лечения НБ высокого риска ознаменовала собой значительный прогресс в улучшении прогноза для пациентов, достигших хорошего ответа на терапию первой линии. В настоящее время Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США (Food and Drug Administration) одобрено 3 препарата мАТ для лечения пациентов с НБ группы высокого риска: динутуксимаб (Ch14.18), динутуксимаб бета (Сh14.18/CHO) и накситамаб (Hu3F8). Настоящая публикация посвящена обзору клинического применения гуманизированного мАТ Hu3F8, эффективность которого была продемонстрирована в рамках клинических исследований.

1. Irwin M.S., Park J.R. Neuroblastoma: paradigm for precision medicine. Pediatr Clin North Am. 2015;62(1):225–56. doi: 10.1016/j.pcl.2014.09.015. PMID: 25435121.

2. Voeller J., Sondel P.M. Advances in anti-GD2 immunotherapy for treatment of high-risk neuroblastoma. J Pediatr Hematol Oncol. 2019;41(3):163–9. doi: 10.1097/MPH.0000000000001369.

3. Berthold F., Faldum A., Ernst A., Boos J., Dilloo D., Eggert A., Fischer M., Frühwald M., Henze G., Klingebiel T., Kratz C., Kremens B., Krug B., Leuschner I., Schmidt M., Schmidt R., Schumacher-Kuckelkorn R., von Schweinitz D., Schilling F.H., Theissen J., Volland R., Hero B., Simon T. Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol. 2020;31(3):422–9. doi: 10.1016/j.annonc.2019.11.011. PMID: 32067684.

4. Sait S., Modak S. Anti-GD2 immunotherapy for neuroblastoma. Expert Rev Anticancer Ther. 2017;17(10):889–904. doi: 10.1080/14737140.2017.1364995.

5. Cheung N.K.V., Guo H., Hu J., Tassev D.V., Cheung I.Y. Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo. Oncoimmunology. 2012;1(4):477–86. doi: 10.4161/onci.19864.

6. Lisby S., Liebenberg N., Bukrinski J., Sonderby P., Lund-Hansen T. Naxitamab, an antibody with distinct complementary determining regions and high binding affi nity to disialoganglioside GD2. Pediatric Blood Cancer. 2020;67:281–2.

7. Danyelza (naxitamab-gqgk). Prescribing Information: 14. Clinical studies. Y-mAbs Therapeutics, Inc.; 25 Nov 2020.

8. ClinicalTrials.gov. [Electronic resource]: https://clinicaltrials.gov/ct2/show/NCT03363373 (accessed – 30 July 2021).

9. Morgenstern D.A., Mora J., Chan G.C., Nysom K., Bear M., Dalby L.W., Kushner B.H. Pivotal trial 201 data on outpatient administration of naxitamab (Hu3F8), a humanized GD2 targeted immunotherapy for the treatment of refractory/relapsed (R/R) highrisk (HR) neuroblastoma (NB). Ann Oncol. 2020;31:1448. doi: 10.1016/j.annonc.2020.10.562.

10. Mora J., Chan G.C., Morgenstern D.A., Nysom K., Bear M., Dalby L.W., Kushner B.H. Effi cacy and updated safety results from pivotal phase II trial 201 of naxitamab (Hu3F8): a humanized GD2- targeted immunotherapy for the treatment of refractory/relapsed (R/R) high-risk (HR) neuroblastoma (NB). Ann Oncol. 2020;31:S1448. doi: 10.1016/j.annonc.2020.10.563.

11. Kushner B.H., Cheung I.Y., Modak S., Basu E.M., Roberts S.S., Cheung N.K. Humanized 3F8 anti-GD2 monoclonal antibody dosing with granulocyte-macrophage colony-stimulating factor in patients with resistant neuroblastoma: a phase 1 clinical trial. JAMA Oncol. 2018;4(12):1729–35. doi: 10.1001/jamaoncol.2018.4005.

12. Mora J., Chan G.C., Morgenstern D.A., Nysom K., Bear M.K., Tornøe K., Kushner B.H. Outpatient administration of naxitamab in combination with granulocyte-macrophage-colony-stimulating factor in patients with refractory and/or relapsed high-risk neuroblastoma: management of adverse events. Cancer Rep (Hoboken). 2022;6(1):e1627. doi: 10.1002/cnr2.1627.

13. Mora J., Castañeda A., Gorostegui M., Santa-María V., Garraus M., Muñoz J.P., Varo A., Perez-Jaume S., Mañe S. Naxitamab combined with granulocyte-macrophage colony-stimulating factor as consolidation for high-risk neuroblastoma patients in complete remission. Pediatr Blood Cancer. 2021;68(10):e29121. doi: 10.1002/pbc.29121. PMID: 34022112.

14. Modak S., Kushner B.H., Mauguen A., Castañeda A., Varo A., Gorostegui M., Muñoz J.P., Santa-Maria V., Basu E.M., Iglesias Cardenas F., Pandit-Taskar N., Cheung N.K.V., Mora J. Naxitamab based chemoimmunotherapy for resistant high-risk neuroblastoma: Results of “HITS” phase II study. J Clin Oncol. 2022;10028. doi: 10.1200/JCO.2022.40.16_suppl.10028.

15. Castañeda A., Gorostegui M., Miralles S.L., Chamizo A., Patiño S.C., Flores M.A., Garraus M., Lazaro J.J., Santa-Maria V., Varo A., Muñoz J.P., Mora J. How we approach the treatment of patients with high-risk neuroblastoma with naxitamab: experience from the Hospital Sant Joan de Déu in Barcelona, Spain. ESMO Open. 2022;7(2):100462. doi: 10.1016/j.esmoop.2022.100462. Erratum in: ESMO Open. 2022;7(3):100504. doi: 10.1016/j.esmoop.2022.100504. PMID: 35397431; PMCID: PMC9006652.

16. Unituxin (dinutuximab) injection, for intravenous use prescribing information (2020). [Electronic resource]: https://unituxin.com/fullprescribing-information.pdf. (accessed – 20.06.2026).

17. Qarziba (dinutuximab beta) summary of product characteristics (2020). [Electronic resource]: https://www.ema.europa.eu/en/documents/product-information/qarziba-epar-product-information_en.pdf. (accessed – 20.06.2026).

18. Ladenstein R.L., Pötschger U., Valteau-Couanet D., Luksch R., Castel V., Yaniv I., Laureys G., Brock P., Michon J.M., Owens C., Trahair T., Chi Fung Chan G., Ruud E., Schroeder H., Beck Popovic M., Schreier G., Loibner H., Ambros P., Holmes K., Castellani M.R., Gaze M.N., Garaventa A., Pearson A.D.J., Lode H.N. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1617–29. doi: 10.1016/S1470-2045(18)30578-3.

19. Barone G., Barry A., Bautista F., Brichard B., Defachelles A.-S., Herd F., Manzitti C., Reinhardt D., Rubio P.M., Wieczorek A., van Noesel M.M. Managing adverse events associated with dinutuximab beta treatment in patients with high-risk neuroblastoma: practical guidance. Paediatr Drugs. 2021;23:537–48.

20. Varo A., Castañeda A., Chamorro S., Muñoz J.P., Gorostegui M., Celma M.S., Lopez S., Simao M., Perez-Jaume S., Mora J. Novel infusion strategy reduces severe adverse events caused by the antiGD2 monoclonal antibody naxitamab. Front Oncol. 2023;13:1164949. doi: 10.3389/fonc.2023.1164949. PMID: 37213300; PMCID: PMC10196122.

21. Tong W., Maira M., Gagnon M., Saragovi H.U. Ligands binding to cell surface ganglioside GD2 cause src-dependent activation of N-methylD-aspartate receptor signaling and changes in cellular morphology. PLoS One. 2015;10(8):e0134255. doi: 10.1371/journal.pone.0134255. PMID: 26252487; PMCID: PMC4529173.

22. George S., Johns M. Review of nonopioid multimodal analgesia for surgical and trauma patients. Am J Health Syst Pharm. 2020;77(24):2052–63. doi: 10.1093/ajhp/zxaa301. PMID: 33037818.

23. Electronic medicines compendium ketalar summary of product characteristics (SmPC). [Electronic resource]: https://www.medicines.org.uk/emc/product/2231/smpc#gref. (accessed – 20.06.2026).

24. Kushner B.H., Modak S., Kramer K., Basu E.M., Iglesias-Cardenas F., Roberts S.S., Cheung N.V. Immunotherapy with anti-GD2 monoclonal antibody in infants with high-risk neuroblastoma. Int J Cancer. 2023;152(2):259–66. doi: 10.1002/ijc.34233.

25. Cheung I.Y., Kushner B.H., Modak S., Basu E.M., Roberts S.S., Cheung N.V. Phase I trial of anti-GD2 monoclonal antibody hu3F8 plus GM-CSF: Impact of body weight, immunogenicity and anti-GD2 response on pharmacokinetics and survival. Oncoimmunology. 2017;6(11):e1358331. doi: 10.1080/2162402X.2017.1358331. PMID: 29147617; PMCID: PMC5674972.

26. Mora J., Castañeda A., Gorostegui M., Varo A., Perez-Jaume S., Simao M., Muñoz J.P., Garraus M., Larrosa C., Salvador N., Lavarino C., Krauel L., Mañe S. Naxitamab Combined with Granulocyte-Macrophage Colony-Stimulating Factor as Consolidation for High-Risk Neuroblastoma Patients in First Complete Remission under Compassionate Use-Updated Outcome Report. Cancers (Basel). 2023;15(9):2535. doi: 10.3390/cancers15092535.

27. Mora J., Chan G.C.F., Morgenstern D.A., Amoroso L., Nysom K., Faber J., Wingerter A., Bear M.K., Rubio-San-Simon A., de Las Heras B.M., Tornøe K., Düring M., Kushner B.H. The antiGD2 monoclonal antibody naxitamab plus GM-CSF for relapsed or refractory high-risk neuroblastoma: a phase 2 clinical trial. Nat Commun. 2025;16(1):1636. doi: 10.1038/s41467-025-56619-x. PMID: 39952926; PMCID: PMC11828896.

28. Lode H.N., Holko P., Wieczorek A., Siebert N., Valteau-Couanet D., Garaventa A., Cañete A., Anderson J., Yaniv I., Ash S., Gray J., Luksch R., Manzitti C., Troschke-Meurer S., Ebeling T., Kawalec P., Śladowska K., Ladenstein R.L. Dinutuximab beta versus naxitamab in the treatment of relapsed/refractory neuroblastoma in patients with stable disease, minor response or partial response and disease in bone or bone marrow: systematic review and matching-adjusted indirect comparison. Cancers (Basel). 2025;17(17):2723. doi: 10.3390/cancers17172723. PMID: 40940820; PMCID: PMC12427561.

29. Wei W., Fader M.E., Kushner B.H., Cardenas F.I., Kramer K., Basu E., Modak S. Pulmonary toxicity associated with concurrent lorlatinib and anti-GD2 monoclonal antibody therapy in patients with neuroblastoma. Pediatr Blood Cancer. 2025;72(9):e31845. doi: 10.1002/pbc.31845.