Velayudhan Jyoti, Chen Yuh-Feng, Rohrbach Amanda, Pastula Christina, Maher Gwen, Thomas Heather, Brown Ryan, Born Teresa L
Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA, 91320, USA.
BioDrugs. 2016 Aug;30(4):339-51. doi: 10.1007/s40259-016-0185-2.
Due to the complex molecular structure and proprietary manufacturing processes of monoclonal antibodies (mAbs), differences in structure and function may be expected during development of biosimilar mAbs. Important regulatory requirements for approval of biosimilar products involve comprehensive assessments of any potential differences between proposed biosimilars and reference mAbs, including differences in all known mechanisms of action, using sensitive and relevant methods. Any identified structural differences should not result in differences in biofunctional or clinical activity.
A comprehensive assessment comparing the Amgen biosimilar candidate ABP 501 with FDA-licensed adalimumab (adalimumab [US]) and EU-authorized adalimumab (adalimumab [EU]) was conducted to demonstrate similarity in biofunctional activity.
The functional similarity assessment included testing of binding kinetics to soluble tumor necrosis factor α (TNFα) and relative binding to transmembrane TNFα. The neutralization of TNFα-induced caspase activation, TNFα- and lymphotoxin-α (LTα)-induced chemokine production, and cytotoxicity was also tested. Binding to Fc-gamma receptors FcγRIa, FcγRIIa (131H), FcγRIIIa (158V and 158F), and neonatal Fc receptor (FcRn) was compared with the reference mAbs, as was antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity.
The data demonstrate that ABP 501 is similar to both adalimumab (US) and adalimumab (EU) with respect to evaluated biofunctional activities.
Similarity in biofunctional activity is a critical component of the totality of evidence required for demonstration of biosimilarity. The functional similarity demonstrated for ABP 501 comprehensively assesses the known mechanisms of action of adalimumab, supporting the conclusion that ABP 501, adalimumab (US), and adalimumab (EU) are likely to be clinically similar.
由于单克隆抗体（mAb）的分子结构复杂且生产工艺独特，在生物类似药单克隆抗体的研发过程中，其结构和功能可能会存在差异。生物类似药产品获批的重要监管要求包括，使用灵敏且相关的方法，全面评估拟议的生物类似药与参比单克隆抗体之间的任何潜在差异，包括所有已知作用机制的差异。任何已确定的结构差异都不应导致生物功能或临床活性的差异。
对安进公司的生物类似药候选药物ABP 501与美国食品药品监督管理局（FDA）批准的阿达木单抗（阿达木单抗[美国]）和欧盟批准的阿达木单抗（阿达木单抗[欧盟]）进行全面评估，以证明其生物功能活性相似。
功能相似性评估包括检测与可溶性肿瘤坏死因子α（TNFα）的结合动力学以及与跨膜TNFα的相对结合。还测试了TNFα诱导的半胱天冬酶激活的中和作用、TNFα和淋巴毒素α（LTα）诱导的趋化因子产生以及细胞毒性。将与FcγRIa、FcγRIIa（131H）、FcγRIIIa（158V和158F）和新生儿Fc受体（FcRn）的结合与参比单克隆抗体进行比较，同时比较抗体依赖性细胞介导的细胞毒性和补体依赖性细胞毒性。
数据表明，ABP 501在评估的生物功能活性方面与阿达木单抗（美国）和阿达木单抗（欧盟）相似。
生物功能活性相似性是证明生物相似性所需全部证据的关键组成部分。ABP 501所显示的功能相似性全面评估了阿达木单抗的已知作用机制，支持ABP 501、阿达木单抗（美国）和阿达木单抗（欧盟）在临床上可能相似的结论。
