The First WHO International Standard for Adalimumab: Dual Role in Bioactivity and Therapeutic Drug Monitoring

Abstract

The expanded availability of adalimumab products continues to widen patient access and reduce costs with substantial benefit to healthcare systems. However, the long-term success of these medicines is highly dependent on maintaining consistency in quality, safety and efficacy while minimizing any risk of divergence during life-cycle management. In recognition of this need and demand from global manufacturers, the World Health Organization (WHO) Expert Committee on Biological standardization established the WHO 1st International standard (IS) for Adalimumab (coded 17/236) in October 2019 with a defined unitage ascribed to each of the individual bioactivities evaluated in the study namely, TNF-α binding, TNF-α neutralization, complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity. For development of the IS, two candidate standards were manufactured as per WHO recommendations. Analysis of extensive datasets generated by testing of a common set of samples including the candidate standards by multiple stakeholders including regulatory agencies using their own qualified assays in a large international collaborative study showed comparable biological activity for the tested candidates for the different activities. Use of a common standard significantly decreased the variability of bioassays and improved agreement in potency estimates. Data from this study clearly supports the utility of the IS as an important tool for assuring analytical assay performance, for bioassay calibration and validation, for identifying and controlling changes in bioactivity during life-cycle management and for global harmonization of adalimumab products. In addition, in a separate multi-center study which included involvement of hospital and clinical diagnostic laboratories, the suitability of the adalimumab IS for therapeutic drug monitoring assays was examined by analysis of data from testing of a common blind coded panel of adalimumab spiked serum samples representative of the clinical scenario along with the IS and in-house standards in diverse immunoassays/platforms. Both commercially available and in-house assays that are routinely used for assessing adalimumab trough levels were included. Excellent agreement in estimates for adalimumab content in the spiked samples was observed regardless of the standard or the method with inter-laboratory variability also similar regardless of the standard employed. This data, for the first time, provides support for the extended applicability of the IS in assays in use for therapeutic drug monitoring based on the mass content of the IS. The adalimumab IS, in fulfilling clinical demand, can help toward standardizing and harmonizing clinical monitoring assays for informed clinical decisions and/or personalized treatment strategies for better patient outcomes. Collectively, a significant role for the adalimumab IS in assuring the quality, safety and efficacy of adalimumab products globally is envisaged.

The First WHO International Standard for Harmonizing the Biological Activity of Bevacizumab

“…Although both formulations proved to be suitable, Formulation A was selected for the final lyophilization of the three preparations ( Table 3 ) as this retained marginally more biological activity relative to the bulk material in comparison with Formulation B in both bioassays and binding assays (data not shown). Formulation A with sodium citrate and human serum albumin as excipients has been used previously for WHO ISs for mAbs, e.g., Infliximab IS and Adalimumab IS [ 38 , 39 ]. As shown in Table 3 , all parameters of ampoule integrity were within the specifications required by the WHO for long-term stability.…”

“…The WHO Expert Committee on Biological Standardization (ECBS) recognized this need and endorsed the initiation of IS development for these products in October 2016 [ 36 ]. To fulfil NIBSC’s mission in assuring the quality of biological medicines [ 37 , 38 , 39 ], we produced lyophilized Bevacizumab preparations, including a candidate standard, and organised an international collaborative study with the aims of (i) developing a WHO IS for Bevacizumab by assessing the suitability of the candidate preparation to serve as a “reference standard” for bioactivity determination of Bevacizumab products and (ii) assigning international units of activity to the different functionalities of the proposed Bevacizumab IS.…”

International standards for monoclonal antibodies for assessing the biological activity of medicines: A status update

“…В отчетах о результатах международных исследований по разработке и изучению МСО этанерцепта, ритуксимаба, инфликсимаба, ада лимумаба, бевацизумаба, трастузумаба 16 и цетуксимаба 17 отмечается, что применение в соответствующих биологических тестах препаратовкандидатов в МСО, в отличие от внутренних СО производителей, способствовало гармонизации оценки биологической активности между лабораториями даже при использовании нескольких методик, основанных на разных принципах [25,28,[32][33][34].…”

“…Проявление активности адалимумаба может быть обусловлено и Fc-опосредованными механизмами, такими как ADCC и CDC [33,40]. Следует отметить, что, несмотря на достижение клинического эффекта при применении препарата, имеются опасения по поводу нежелательной иммуногенности и снижения эффективности, которые отмечены для других ингибиторов TNF-α [41].…”

“…Для определения активности адалимумаба применяли анализ репортерного гена в тесте подавления TNFстимулированной активации фактора транскрипции NF-κB, оцениваемой путем измерения активности люциферазы или секретированной эмбриональной щелочной фосфатазы в клетках линии HEK-293, трансфицированной конструкциями репортерного гена. Ингибирование апоптоза, опосредованного TNF-α, оценивали путем изучения активности каспаз в клетках линии U937 [33,44]. Для оценки Fc-эффекторной функции адалимумаба в исследование были включены тесты CDC и ADCC [33].…”