Adalimumab, a recombinant fully human monoclonal antibody targeting tumor necrosis factor (TNF), is approved in the United States and Europe to treat various inflammatory and autoimmune indications. Biosimilars are approved biologics highly similar, but not identical, to approved biotherapeutics. To support clinical development of PF-06410293, an adalimumab biosimilar, nonclinical studies evaluated the structural, functional, toxicologic, and toxicokinetic similarity to originator adalimumab sourced from the United States (adalimumab-US) and European Union (adalimumab-EU). Structural similarity was assessed by peptide mapping. Biologic activity was measured via inhibition of TNF-induced apoptosis and Fc-based functionality assessments. In vivo nonclinical similarity was evaluated in a toxicity study in cynomolgus monkeys administered subcutaneous PF-06410293 or adalimumab-EU (0 or 157 mg/kg/week). Peptide mapping demonstrated PF-06410293, adalimumab-US, and adalimumab-EU had identical amino acid sequences. Comparative functional and binding assessments were similar. Effects of PF-06410293 and adalimumab-EU were similar and limited to pharmacologically mediated decreased cellularity of lymphoid follicles and germinal centers in spleen. Toxicokinetics were similar; maximum plasma concentration and area-under-the-concentration-time curve ratio of PF-06410293:adalimumab-EU ranged from 1.0 to 1.2. These studies supported PF-06410293 entry into clinical development. Many regulatory agencies now only request nonclinical in vivo testing if there is residual uncertainty regarding biosimilarity after in vitro analytical studies.

中文翻译：

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生物仿制药PF-06410293和鼻祖阿达木单抗的比较非临床评估。

阿达木单抗是一种靶向肿瘤坏死因子（TNF）的重组全人类单克隆抗体，已在美国和欧洲获得批准，可用于治疗各种炎症和自身免疫适应症。生物仿制药是经批准的生物制剂，与批准的生物治疗药物高度相似，但不完全相同。为了支持PF-06410293的临床开发，阿达木单抗生物仿制药的非临床研究评估了与美国（adalimumab-US）和欧盟（adalimumab-EU）的原始阿达木单抗的结构，功能，毒理学和毒物动力学相似性。通过肽作图评估结构相似性。通过抑制TNF诱导的细胞凋亡和基于Fc的功能评估来测量生物活性。在毒性研究中评估了皮下注射PF-06410293或阿达木单抗-EU（0或157 mg / kg /周）的食蟹猴的体内非临床相似性。肽图分析表明PF-06410293，阿达木单抗-US和阿达木单抗-EU具有相同的氨基酸序列。比较功能和约束力评估相似。PF-06410293和阿达木单抗-EU的作用相似，并且仅限于药理学上介导的淋巴滤泡和脾生发中心细胞减少。毒代动力学相似。PF-06410293：阿达木单抗-EU的最大血浆浓度和浓度下时间曲线的比率在1.0到1.2之间。这些研究支持PF-06410293进入临床开发。