biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2023-23-4-480-498biopreparat-532Research ArticleОБЗОРЫREVIEWSМеждународные стандартные образцы моноклональных антител для оценки биологической активности лекарственных препаратов: современное состояниеInternational standards for monoclonal antibodies for assessing the biological activity of medicines: A status updatehttps://orcid.org/0000-0002-6176-5934ГайдероваЛ. А.GayderovaL. A.

Гайдерова Лидия Александровна, канд. мед. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Lidia A. Gayderova, Cand. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

gaiderova@expmed.ruhttps://orcid.org/0000-0002-6807-508XАлпатоваН. А.AlpatovaN. A.

Алпатова Наталья Александровна, д-р биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Natalia А. Alpatova, Dr. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

alpatova@expmed.ruhttps://orcid.org/0000-0001-7864-8972ЛысиковаС. Л.LysikovaS. L.

Лысикова Светлана Леонидовна, канд. мед. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Svetlana L. Lysikova, Cand. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

lisikova@expmed.ruhttps://orcid.org/0000-0001-9889-4038БайковаМ. Л.BaykovaM. L.

Байкова Марина Леонидовна

Петровский б-р, д. 8, стр. 2, Москва, 127051

Marina L. Baykova

8/2 Petrovsky Blvd, Moscow 127051

baikova@expmed.ruhttps://orcid.org/0000-0003-4523-5316ГуськовА. М.GuskovA. M.

Гуськов Александр Михайлович

Петровский б-р, д. 8, стр. 2, Москва, 127051

Alexander M. Guskov

8/2 Petrovsky Blvd, Moscow 127051

Guskov@expmed.ruhttps://orcid.org/0000-0002-6970-1732ЗубковД. А.ZubkovD. A.

Зубков Дмитрий Анатольевич

Петровский б-р, д. 8, стр. 2, Москва, 127051

Dmitriy A. Zubkov

8/2 Petrovsky Blvd, Moscow 127051

Zubkov@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian Federation202317122023234480498Copyright © Гайдерова Л.А., Алпатова Н.А., Лысикова С.Л., Байкова М.Л., Гуськов А.М., Зубков Д.А., 20232023Гайдерова Л.А., Алпатова Н.А., Лысикова С.Л., Байкова М.Л., Гуськов А.М., Зубков Д.А.Gayderova L.A., Alpatova N.A., Lysikova S.L., Baykova M.L., Guskov A.M., Zubkov D.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/532Актуальность

Актуальность. Эффект клинического применения биотехнологических препаратов на основе моноклональных антител (МкАТ) и истечение срока действия патентов на оригинальные (референтные) препараты стимулировали разработку биоаналогичных МкАТ, профиль качества которых должен соответствовать качеству референтного лекарственного средства. Изучение биологических свойств МкАТ при доказательстве биоподобия и определение активности препаратов в рамках контроля качества серий необходимо проводить с использованием подходящих стандартных образцов (СО). В связи с отсутствием международных стандартов производители препаратов МкАТ применяют собственные стандартные образцы, но, учитывая сложную структуру и гетерогенность МкАТ, а также наличие связи между биологической активностью и клинической эффективностью, нельзя исключить наличие риска расхождения данных о качестве и эффективности препаратов.

Цель

Цель. Анализ сведений об актуальности и необходимости разработки международных стандартных образцов (МСО) для определения биологической активности биотерапевтических МкАТ, о роли референтных препаратов и МСО при оценке сходства/подобия, а также на разных этапах жизненного цикла биоаналогичных препаратов МкАТ.

Обсуждение

Обсуждение. Рассмотрены проблемы, связанные с отсутствием МСО для оценки активности препаратов МкАТ. Приведены сведения о роли и значимости референтных препаратов и МСО для биоаналогичных препаратов. Представлена информация об особенностях изучения биологических свойств МкАТ и обобщены данные о необходимости разработки и применения МСО для стандартизации биологических тестов. В обзоре представлены результаты исследований первых утвержденных ВОЗ международных стандартных образцов для оценки биологической активности МкАТ, свидетельствующие о необходимости стандартизации препаратов МкАТ с использованием МСО для обеспечения их качества, безопасности и эффективности.

Заключение

Заключение. Применение МСО для препаратов МкАТ играет ключевую роль в гармонизации подходов к оценке их биологической активности. Общедоступные МСО препаратов МкАТ необходимы как первичные СО для аттестации вторичных СО, для гармонизации подходов к оценке активности МкАТ (в международных единицах) между лабораториями, а также для согласования активности препаратов одного международного непатентованного наименования разных производителей. Использование МСО производителями МкАТ будет способствовать гарантии качества препаратов МкАТ и обеспечению клинического мониторинга эффективности их применения.

Scientific relevance

Scientific relevance. The clinical effects and the expiration of patents for original (reference) biotechnological medicines based on monoclonal antibodies (mAbs) stimulated the development of biosimilar mAbs. The quality profile of a biosimilar mAb should correspond to the quality of the reference medicinal product. When demonstrating biosimilarity and determining the activity of medicines as part of batch quality control, analysts should study the biological properties of mAbs using suitable reference standards. The lack of international standards (ISs) makes mAb manufacturers use in-house reference standards. There is a risk of obtaining non-uniform quality and efficacy data because of the use of in-house reference standards, the heterogeneity and structural complexity of mAbs, and the relationship between the biological activity and efficacy of mAbs.

Aim

Aim. This study aimed to analyse the relevance of and need for ISs for the biological activity of biotherapeutic mAbs and to define the role of reference medicinal products and ISs in assessing biosimilarity and testing medicines throughout their lifecycle.

Discussion

Discussion. This review covers the issues arising from the lack of ISs for assessing the biological activity of mAbs and the role and significance of reference products and ISs for biosimilars. The authors describe the specifics of studying the biological properties of mAbs and summarise the data on the need to develop and use ISs for the standardisation of biological tests. This review presents the results of studies on the first ISs established by the World Health Organisation to assess the biological activity of mAbs; these results suggest the need to standardise mAbs using ISs to ensure the quality, safety, and efficacy of mAb therapy.

Conclusions

Conclusions. The use of ISs for mAbs plays a key role in harmonising biological activity assessments. Publicly available ISs serve as primary standards for the calibration of secondary reference materials. Moreover, ISs are required for the harmonisation of activity evaluation (in IU) between laboratories and for the consistency of the activity of various medicinal products from different manufacturers that share the same INN. The use of ISs by mAb manufacturers will contribute to ensuring the quality of mAbs and clinical monitoring of the effectiveness of their use.

моноклональные антителатерапевтические белкимеждународные стандартные образцыбиоподобиебиоаналогичные (биоподобные) препаратыреферентный препараткачествобиологическая активностьэффективностьбиологические тестыmonoclonal antibodiesmAbstherapeutic proteinsinternational standardsbiosimilaritybiosimilarsreference medicinal productqualitybiological activityefficacybiological testsРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00052-23-00 на проведение прикладных научных исследований (номер государственного учета НИР 121022000147-4).The study reported in this publication was carried out as part of publicly funded research project No. 056-00052-23-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D reporting No. 121022000147-4).ReferencesLe Basle Y, Chennell P, Tokhadze N, Astier A, Sautou V. Physicochemical stability of monoclonal antibodies: a review. J Pharm Sci. 2020;109(1):169–90. https://doi.org/10.1016/j.xphs.2019.08.009Le Basle Y, Chennell P, Tokhadze N, Astier A, Sautou V. Physicochemical stability of monoclonal antibodies: a review. J Pharm Sci. 2020;109(1):169–90. https://doi.org/10.1016/j.xphs.2019.08.009Nupur N, Joshi S, Gulliarme D, Rathore AS. Analytical similarity assessment of biosimilars: global regulatory landscape, recent studies and major advancements in orthogonal platforms. Front Bioeng Biotechnol. 2022;10:832059. https://doi.org/10.3389/fbioe.2022.832059Nupur N, Joshi S, Gulliarme D, Rathore AS. Analytical similarity assessment of biosimilars: global regulatory landscape, recent studies and major advancements in orthogonal platforms. Front Bioeng Biotechnol. 2022;10:832059. https://doi.org/10.3389/fbioe.2022.832059Авдеева ЖИ, Солдатов АА, Алпатова НА, Медуницын НВ, Бондарев ВП, Миронов АН и др. Лекарственные препараты моноклональных антител нового поколения (проблемы и перспективы). БИОпрепараты. Профилактика, диагностика, лечение. 2015;(1):21–35. EDN: UBEKGDAvdeeva ZhI, Soldatov AA, Alpatova NA, Medunitsyn NV, Bondarev VP, Mironov AN, et al. Preparations of next generation monoclonal antibodies (issues and prospects). Biopreparation (Biopharmaceuticals). 2015;(1):21–35 (In Russ.). EDN: UBEKGDLee CC, Perchiacca JM, Tessier PM. Toward aggregation-resistant antibodies by design. Trends Biotechnol. 2013;31(11):612–20. https://doi.org/10.1016/j.tibtech.2013.07.002Lee CC, Perchiacca JM, Tessier PM. Toward aggregation-resistant antibodies by design. Trends Biotechnol. 2013;31(11):612–20. https://doi.org/10.1016/j.tibtech.2013.07.002Alhazmi HA, Albratty M. Analytical techniques for the characterization and quantification of monoclonal antibodies. Pharmaceuticals (Basel). 2023;16(2):291. https://doi.org/10.3390/ph16020291Alhazmi HA, Albratty M. Analytical techniques for the characterization and quantification of monoclonal antibodies. Pharmaceuticals (Basel). 2023;16(2):291. https://doi.org/10.3390/ph16020291Алпатова НА, Гайдерова ЛА, Яковлев АК, Мотузова ЕВ, Лысикова СЛ, Солдатов АА и др. Особенности определения специфической активности биотехнологических лекарственных средств. Биопрепараты. Профилактика, диагностика, лечение. 2017;17(1):13–26. EDN: YHSSGLAlpatova NA, Gayderova LA, Yakovlev AK, Motuzova EV, Lysikova SL, Soldatov AA et al. Assessment of biotechnological products’ specific activity. BIOpreparations. Prevention, Diagnosis, Treatment. 2017;17(1):13–26 (In Russ.). EDN: YHSSGLMimura Y, Katoh T, Saldova R, O’Flaherty R, Izumi T, Mimura-Kimura Y, et al. Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy. Protein Cell. 2018;9(1):47–62. https://doi.org/10.1007/s13238-017-0433-3Mimura Y, Katoh T, Saldova R, O’Flaherty R, Izumi T, Mimura-Kimura Y, et al. Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy. Protein Cell. 2018;9(1):47–62. https://doi.org/10.1007/s13238-017-0433-3Dash R, Singh SK, Chirmule N, Rathore AS. Assessment of functional characterization and comparability of biotherapeutics: a review. AAPS J. 2021;24(1):15. https://doi.org/10.1208/s12248-021-00671-0Dash R, Singh SK, Chirmule N, Rathore AS. Assessment of functional characterization and comparability of biotherapeutics: a review. AAPS J. 2021;24(1):15. https://doi.org/10.1208/s12248-021-00671-0Láng JA, Balogh ZC, Nyitrai MF, Juhász C, Gilicze AKB, Iliás A, et al. In vitro functional characterization of biosimilar therapeutic antibodies. Drug Discov Today Technol. 2020;37:41–50. https://doi.org/10.1016/j.ddtec.2020.11.010Láng JA, Balogh ZC, Nyitrai MF, Juhász C, Gilicze AKB, Iliás A, et al. In vitro functional characterization of biosimilar therapeutic antibodies. Drug Discov Today Technol. 2020;37:41–50. https://doi.org/10.1016/j.ddtec.2020.11.010Wang X, An Z, Luo W, Xia N, Zhao Q. Molecular and functional analysis of monoclonal antibodies in support of biologics development. Protein Cell. 2018;9(1):74–85. https://doi.org/10.1007/s13238-017-0447-xWang X, An Z, Luo W, Xia N, Zhao Q. Molecular and functional analysis of monoclonal antibodies in support of biologics development. Protein Cell. 2018;9(1):74–85. https://doi.org/10.1007/s13238-017-0447-xWild D, ed. The immunoassay handbook: theory and applications of ligand binding, ELISA and related techniques. 4th ed. Elsevier Science; 2013.Wild D, ed. The immunoassay handbook: theory and applications of ligand binding, ELISA and related techniques. 4th ed. Elsevier Science; 2013.Lebakken CS, Riddle SM, Singh U, Frazee WJ, Eliason HC, Gao Y, et al. Development and applications of a broad-coverage, TR-FRET-based kinase binding assay platform. J Biomol Screen. 2009;14(8):924–35. https://doi.org/10.1177/1087057109339207Lebakken CS, Riddle SM, Singh U, Frazee WJ, Eliason HC, Gao Y, et al. Development and applications of a broad-coverage, TR-FRET-based kinase binding assay platform. J Biomol Screen. 2009;14(8):924–35. https://doi.org/10.1177/1087057109339207Noto A, Ngauv P, Trautmann L. Cell-based flow cytometry assay to measure cytotoxic activity. J Vis Exp. 2013;82:e51105. https://doi.org/10.3791/51105Noto A, Ngauv P, Trautmann L. Cell-based flow cytometry assay to measure cytotoxic activity. J Vis Exp. 2013;82:e51105. https://doi.org/10.3791/51105Schasfoort RBM. Handbook of surface plasmon resonance. 2nd ed. RSC Publishing; 2017. https://doi.org/10.1039/9781788010283Schasfoort RBM. Handbook of surface plasmon resonance. 2nd ed. RSC Publishing; 2017. https://doi.org/10.1039/9781788010283Beyer B, Schuster M, Jungbauer A, Lingg N. Micro-heterogeneity of recombinant antibodies: analytics and functional impact. Biotechnol J. 2018;13(1). https://doi.org/10.1002/biot.201700476Beyer B, Schuster M, Jungbauer A, Lingg N. Micro-heterogeneity of recombinant antibodies: analytics and functional impact. Biotechnol J. 2018;13(1). https://doi.org/10.1002/biot.201700476Rosales C. Fcγ receptor heterogeneity in leukocyte functional responses. Front Immunol. 2017;8:280. https://doi.org/10.3389/fimmu.2017.00280Rosales C. Fcγ receptor heterogeneity in leukocyte functional responses. Front Immunol. 2017;8:280. https://doi.org/10.3389/fimmu.2017.00280Branstetter E, Duff RJ, Kuhns S, Padaki R. Fc glycan sialylation of biotherapeutic monoclonal antibodies has limited impact on antibody-dependent cellular cytotoxicity. FEBS Open Bio. 2021;11(11):2943–9. https://doi.org/10.1002/2211-5463.13267Branstetter E, Duff RJ, Kuhns S, Padaki R. Fc glycan sialylation of biotherapeutic monoclonal antibodies has limited impact on antibody-dependent cellular cytotoxicity. FEBS Open Bio. 2021;11(11):2943–9. https://doi.org/10.1002/2211-5463.13267Velasco-Velázquez MA, Salinas-Jazmín N, HisakiItaya E, Cobos-Puc L, Xolalpa W, González G, et al. Extensive preclinical evaluation of an infliximab biosimilar candidate. Eur J Pharm Sci. 2017;102:35–45. https://doi.org/10.1016/j.ejps.2017.01.038Velasco-Velázquez MA, Salinas-Jazmín N, HisakiItaya E, Cobos-Puc L, Xolalpa W, González G, et al. Extensive preclinical evaluation of an infliximab biosimilar candidate. Eur J Pharm Sci. 2017;102:35–45. https://doi.org/10.1016/j.ejps.2017.01.038Eon-Duval A, Broly H, Gleixner R. Quality attributes of recombinant therapeutic proteins: an assessment of impact on safety and efficacy as part of a quality by design development approach. Biotechnol Prog. 2012;28(3):608–22. https://doi.org/10.1002/btpr.1548Eon-Duval A, Broly H, Gleixner R. Quality attributes of recombinant therapeutic proteins: an assessment of impact on safety and efficacy as part of a quality by design development approach. Biotechnol Prog. 2012;28(3):608–22. https://doi.org/10.1002/btpr.1548Ishii-Watabe A, Kuwabara T. Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies. Drug Metab Pharmacokinet. 2019;34(1):64–70. https://doi.org/10.1016/j.dmpk.2018.11.004Ishii-Watabe A, Kuwabara T. Biosimilarity assessment of biosimilar therapeutic monoclonal antibodies. Drug Metab Pharmacokinet. 2019;34(1):64–70. https://doi.org/10.1016/j.dmpk.2018.11.004Prior S, Metcalfe C, Hufton SE, Wadhwa M, Schneider CK, Burns C. Maintaining standards for biosimilar monoclonal antibodies. Nat Biotechnol. 2021;39(3):276–280. https://doi.org/10.1038/s41587-021-00848-0Prior S, Metcalfe C, Hufton SE, Wadhwa M, Schneider CK, Burns C. Maintaining standards for biosimilar monoclonal antibodies. Nat Biotechnol. 2021;39(3):276–280. https://doi.org/10.1038/s41587-021-00848-0Vezér B, Buzás Z, Sebeszta M, Zrubka Z. Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents. Curr Med Res Opin. 2016;32(5):829–34. https://doi.org/10.1185/03007995.2016.1145579Vezér B, Buzás Z, Sebeszta M, Zrubka Z. Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents. Curr Med Res Opin. 2016;32(5):829–34. https://doi.org/10.1185/03007995.2016.1145579Acha V, Mestre-Ferrandiz J. Translating European regulatory approval into healthcare uptake for biosimilars: the second translational gap. Technol Anal Strateg Manag. 2017;29(3):263–75. https://doi.org/10.1080/09537325.2017.1285396Acha V, Mestre-Ferrandiz J. Translating European regulatory approval into healthcare uptake for biosimilars: the second translational gap. Technol Anal Strateg Manag. 2017;29(3):263–75. https://doi.org/10.1080/09537325.2017.1285396Alsamil AM, Giezen TJ, Egberts TC, Doevendans E, Leufkens HG, Gardarsdottir H. Nature and timing of post-approval manufacturing changes of tumour necrosis factor α inhibitor products: a 20-year follow-up study of originators and biosimilars. Eur J Pharm Sci. 2022;175:106227. https://doi.org/10.1016/j.ejps.2022.106227Alsamil AM, Giezen TJ, Egberts TC, Doevendans E, Leufkens HG, Gardarsdottir H. Nature and timing of post-approval manufacturing changes of tumour necrosis factor α inhibitor products: a 20-year follow-up study of originators and biosimilars. Eur J Pharm Sci. 2022;175:106227. https://doi.org/10.1016/j.ejps.2022.106227Prior S, Hufton SE, Fox B, Dougall T, Rigsby P, Bristow A. International standards for monoclonal antibodies to support pre- and post-marketing product consistency: evaluation of a candidate international standard for the bioactivities of rituximab. MAbs. 2018;10(1):129–42. https://doi.org/10.1080/19420862.2017.1386824Prior S, Hufton SE, Fox B, Dougall T, Rigsby P, Bristow A. International standards for monoclonal antibodies to support pre- and post-marketing product consistency: evaluation of a candidate international standard for the bioactivities of rituximab. MAbs. 2018;10(1):129–42. https://doi.org/10.1080/19420862.2017.1386824Thorpe R, Wadhwa M. Intended use of reference products & WHO international standards/ reference reagents in the development of similar biological products (biosimilars). Biologicals. 2011;39(5):262–5. https://doi.org/10.1016/j.biologicals.2011.06.005Thorpe R, Wadhwa M. Intended use of reference products & WHO international standards/ reference reagents in the development of similar biological products (biosimilars). Biologicals. 2011;39(5):262–5. https://doi.org/10.1016/j.biologicals.2011.06.005Udpa N, Million RP. Monoclonal antibody biosimilars. Nat Rev Drug Discov. 2016;15(1):13–4. https://doi.org/10.1038/nrd.2015.12Udpa N, Million RP. Monoclonal antibody biosimilars. Nat Rev Drug Discov. 2016;15(1):13–4. https://doi.org/10.1038/nrd.2015.12Metcalfe С, Dougall Т, Bird С, Rigsby Р, Behr-Gross М-Е, Wadhwa М. The first World Health Organization International Standard for infliximab products: a step towards maintaining harmonized biological activity. MAbs. 2019;11(1):13–25. https://doi.org/10.1080/19420862.2018.1532766Metcalfe С, Dougall Т, Bird С, Rigsby Р, Behr-Gross М-Е, Wadhwa М. The first World Health Organization International Standard for infliximab products: a step towards maintaining harmonized biological activity. MAbs. 2019;11(1):13–25. https://doi.org/10.1080/19420862.2018.1532766Tebbey PW, Varga A, Naill M, Clewell J, Venema J. Consistency of quality attributes for the glycosylated monoclonal antibody Humira® (adalimumab). MAbs. 2015;7(5):805–11. https://doi.org/10.1080/19420862.2015.1073429Tebbey PW, Varga A, Naill M, Clewell J, Venema J. Consistency of quality attributes for the glycosylated monoclonal antibody Humira® (adalimumab). MAbs. 2015;7(5):805–11. https://doi.org/10.1080/19420862.2015.1073429Kang HN, Thorpe R, Knezevic I. The regulatory landscape of biosimilars: WHO efforts and progress made from 2009 to 2019. Biologicals. 2020;65:1–9. https://doi.org/10.1016/j.biologicals.2020.02.005Kang HN, Thorpe R, Knezevic I. The regulatory landscape of biosimilars: WHO efforts and progress made from 2009 to 2019. Biologicals. 2020;65:1–9. https://doi.org/10.1016/j.biologicals.2020.02.005Lamanna WC, Holzmann J, Cohen HP, Guo X, Schweigler M, Stangler T, et al. Maintaining consistent quality and clinical performance of biopharmaceuticals. Expert Opin Biol Ther. 2018;18(4):369–79. https://doi.org/10.1080/14712598.2018.1421169Lamanna WC, Holzmann J, Cohen HP, Guo X, Schweigler M, Stangler T, et al. Maintaining consistent quality and clinical performance of biopharmaceuticals. Expert Opin Biol Ther. 2018;18(4):369–79. https://doi.org/10.1080/14712598.2018.1421169Wadhwa M, Bird Ch, Dilger P, Rigsby P, Jia H, Behr-Gross ME. Establishment of the first WHO International Standard for etanercept, a TNF receptor II Fc fusion protein: Report of an international collaborative study. J Immunol Methods. 2017;447:14–22. https://doi.org/10.1016/j.jim.2017.03.007Wadhwa M, Bird Ch, Dilger P, Rigsby P, Jia H, Behr-Gross ME. Establishment of the first WHO International Standard for etanercept, a TNF receptor II Fc fusion protein: Report of an international collaborative study. J Immunol Methods. 2017;447:14–22. https://doi.org/10.1016/j.jim.2017.03.007Wadhwa M, Bird C, Atkinson E, Cludts I, Rigsby P. The first WHO international standard for adalimumab: dual role in bioactivity and therapeutic drug monitoring. Front Immunol. 2021;12:636420. https://doi.org/10.3389/fimmu.2021.636420Wadhwa M, Bird C, Atkinson E, Cludts I, Rigsby P. The first WHO international standard for adalimumab: dual role in bioactivity and therapeutic drug monitoring. Front Immunol. 2021;12:636420. https://doi.org/10.3389/fimmu.2021.636420Jia H, Harikumar P, Atkinson E, Rigsby P, Wadhwa M. The first WHO international standard for harmonizing the biological activity of bevacizumab. Biomolecules. 2021;11(11):1610. https://doi.org/10.3390/biom11111610Jia H, Harikumar P, Atkinson E, Rigsby P, Wadhwa M. The first WHO international standard for harmonizing the biological activity of bevacizumab. Biomolecules. 2021;11(11):1610. https://doi.org/10.3390/biom11111610Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol. 2003;49(2 Suppl):105–11. https://doi.org/10.1016/mjd.2003.554Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol. 2003;49(2 Suppl):105–11. https://doi.org/10.1016/mjd.2003.554Tracey D, Klareskog L, Sasso EN, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244–79. https://doi.org/10.1016/j.pharmthera.2007.10.001Tracey D, Klareskog L, Sasso EN, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244–79. https://doi.org/10.1016/j.pharmthera.2007.10.001Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007;44(16):3823–37. https://doi.org/10.1016/j.molimm.2007.06.151Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007;44(16):3823–37. https://doi.org/10.1016/j.molimm.2007.06.151Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene. 2003;22(47):7359–68. https://doi.org/10.1038/sj.onc.1206939Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene. 2003;22(47):7359–68. https://doi.org/10.1038/sj.onc.1206939Salinas-Jazmín N, Medina-Rivero E, Velasco-Velázquez MA. Bioassays for the evaluation of target neutralization and complement-dependent cytotoxicity (CDC) of therapeutic antibodies. Methods Mol Biol. 2022;2313:281–94. https://doi.org/10.1007/978-1-0716-1450-1_17Salinas-Jazmín N, Medina-Rivero E, Velasco-Velázquez MA. Bioassays for the evaluation of target neutralization and complement-dependent cytotoxicity (CDC) of therapeutic antibodies. Methods Mol Biol. 2022;2313:281–94. https://doi.org/10.1007/978-1-0716-1450-1_17Marušič M, Klemenčič A. Adalimumab — general considerations. J Pharmacol Clin Toxicol. 2018;6(2):1104–11.Marušič M, Klemenčič A. Adalimumab — general considerations. J Pharmacol Clin Toxicol. 2018;6(2):1104–11.Roda G, Jharap B, Neeraj N, Colombel JF. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7(1):e135. https://doi.org/10.1038/ctg.2015.63Roda G, Jharap B, Neeraj N, Colombel JF. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7(1):e135. https://doi.org/10.1038/ctg.2015.63Meager A, Leung H, Woolley J. Assays for tumour necrosis factor and related cytokines. J Immunol Methods. 1989;116(1):1–17. https://doi.org/10.1016/0022-1759(89)90306-2Meager A, Leung H, Woolley J. Assays for tumour necrosis factor and related cytokines. J Immunol Methods. 1989;116(1):1–17. https://doi.org/10.1016/0022-1759(89)90306-2Khabar KS, Siddiqui S, Armstrong JA. WEHI-13VAR: a stable and sensitive variant of WEHI 164 clone 13 fibrosarcoma for tumor necrosis factor bioassay. Immunol Lett. 1995;46(1–2):107–10. https://doi.org/10.1016/0165-2478(95)00026-2Khabar KS, Siddiqui S, Armstrong JA. WEHI-13VAR: a stable and sensitive variant of WEHI 164 clone 13 fibrosarcoma for tumor necrosis factor bioassay. Immunol Lett. 1995;46(1–2):107–10. https://doi.org/10.1016/0165-2478(95)00026-2Minafra L, Di Cara G, Albanese NN, Cancemi P. Proteomic differentiation pattern in the U937 cell line. Leuk Res. 2011;35(2):226–36. https://doi.org/10.1016/j.leukres.2010.07.040Minafra L, Di Cara G, Albanese NN, Cancemi P. Proteomic differentiation pattern in the U937 cell line. Leuk Res. 2011;35(2):226–36. https://doi.org/10.1016/j.leukres.2010.07.040Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400. https://doi.org/10.1038/nrd1381Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400. https://doi.org/10.1038/nrd1381Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell. 2019;176(6):1248–64. https://doi.org/10.1016/j.cell.2019.01.021Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell. 2019;176(6):1248–64. https://doi.org/10.1016/j.cell.2019.01.021Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis. 2004;7(4):335–45. https://doi.org/10.1007/s10456-004-8272-2Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis. 2004;7(4):335–45. https://doi.org/10.1007/s10456-004-8272-2Ebbers HC, van Meer PJ, Moors EH, Mantel-Teeuwisse AK, Leufkens HG, Schellekens H. Measures of biosimilarity in monoclonal antibodies in oncology: the case of bevacizumab. Drug Discov Today. 2013;18(17–18):872–9. https://doi.org/10.1016/j.drudis.2013.05.004Ebbers HC, van Meer PJ, Moors EH, Mantel-Teeuwisse AK, Leufkens HG, Schellekens H. Measures of biosimilarity in monoclonal antibodies in oncology: the case of bevacizumab. Drug Discov Today. 2013;18(17–18):872–9. https://doi.org/10.1016/j.drudis.2013.05.004Jefferis R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci. 2009;30(7):356–62. https://doi.org/10.1016/j.tips.2009.04.007Jefferis R. Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci. 2009;30(7):356–62. https://doi.org/10.1016/j.tips.2009.04.007Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianférani S. Characterization of therapeutic antibodies and related products. Anal Chem. 2013;85(2):715–36. https://doi.org/10.1021/ac3032355Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianférani S. Characterization of therapeutic antibodies and related products. Anal Chem. 2013;85(2):715–36. https://doi.org/10.1021/ac3032355Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001;61(12):4744–9. PMID: 11406546Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001;61(12):4744–9. PMID: 11406546Collins DM, O’Donovan N, McGowan PM, O’Sullivan F, Duffy MJ, Crown J. Trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) in HER-2-non-amplified breast cancer cell lines. Ann Oncol. 2012;23(7):1788–95. https://doi.org/10.1093/annonc/mdr484Collins DM, O’Donovan N, McGowan PM, O’Sullivan F, Duffy MJ, Crown J. Trastuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) in HER-2-non-amplified breast cancer cell lines. Ann Oncol. 2012;23(7):1788–95. https://doi.org/10.1093/annonc/mdr484Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene. 2003;22(42):6570–8. https://doi.org/10.1038/sj.onc.1206779Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene. 2003;22(42):6570–8. https://doi.org/10.1038/sj.onc.1206779Vincenzi B, Schiavon G, Silletta M, Santini D, Tonini G. The biological properties of cetuximab. Crit Rev Oncol Hematol. 2008;68(2):93–106. https://doi.org/10.1016/j.critrevonc.2008.07.006Vincenzi B, Schiavon G, Silletta M, Santini D, Tonini G. The biological properties of cetuximab. Crit Rev Oncol Hematol. 2008;68(2):93–106. https://doi.org/10.1016/j.critrevonc.2008.07.006Kimura H, Sakai K, Arao T, Shimoyama T, Tamura T, Nishio K. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 2007;98(8):1275–80. https://doi.org/10.1111/j.1349-7006.2007.00510.xKimura H, Sakai K, Arao T, Shimoyama T, Tamura T, Nishio K. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 2007;98(8):1275–80. https://doi.org/10.1111/j.1349-7006.2007.00510.xBeck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianférani S. Characterization of therapeutic antibodies and related products. Anal Chem. 2013;85(2):715–36. https://doi.org/10.1021/ac3032355Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianférani S. Characterization of therapeutic antibodies and related products. Anal Chem. 2013;85(2):715–36. https://doi.org/10.1021/ac3032355Yazdi MH, Faramarzi MA, Nikfar S, Abdollahi M. A comprehensive review of clinical trials on EGFR inhibitors such as cetuximab and panitumumab as monotherapy and in combination for treatment of metastatic colorectal cancer. Avicenna J Med Biotechnol. 2015;7(4):134–44. PMID: 26605007Yazdi MH, Faramarzi MA, Nikfar S, Abdollahi M. A comprehensive review of clinical trials on EGFR inhibitors such as cetuximab and panitumumab as monotherapy and in combination for treatment of metastatic colorectal cancer. Avicenna J Med Biotechnol. 2015;7(4):134–44. PMID: 26605007

The authors declare that there are no conflicts of interest present.