通过体外免疫原性实验验证重组治疗蛋白中清洁诱导降解物的肠外每日允许暴露值。

IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Journal of pharmaceutical sciences Pub Date : 2024-10-25 DOI:10.1016/j.xphs.2024.10.041
Joseph R Cohen, Marisa K Joubert, Syeda Tabassum, Allyson Capili, Julia Carreon, Cathie Xiang, Siddharth Prabhu, Anthony Merlo, Dan Mytych, David G Dolan, Ram Kouda
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引用次数: 0

摘要

生物治疗蛋白质的多产品生产过程中会产生清洗诱导的蛋白质降解物,因为在清洗过程中会出现极端的 pH 值和温度条件。清洗验收限值是根据先前生产的活性药物成分 (API) 或药物产品的最大允许带入量 (MAC) 评估计算得出的,其依据是先前生产的 API 与后续产品剂量的允许日接触量 (PDE)。在这项研究中,我们测试了之前确定的 650 微克/剂量的清洁诱导蛋白质降解物 PDE 值。我们采用了一种工作台规模的清洗方法,从半衰期延长 (HLE) BiTE® 分子和 mAb 产品中生成清洗诱导降解物。在这项研究中,对 HLE BiTE®-A 和 mAb-1 的降解物进行了单独表征,或将 HLE BiTE®-A 和 mAb-1 的降解物添加到 650 µg 的 mAb-1 中进行表征。通过内毒素测试、尺寸排阻色谱法(SEC)、HIAC 光遮蔽和微流体成像(MFI)对这些样品进行了表征。这些结果表明,由于清洗过程,分子发生了严重降解,不再是完整的形式或活性状态。在 20 小时和 7 天后,使用细胞系测定法评估免疫活化情况,并使用人类外周血单核细胞(PBMC)测定法评估 T 细胞活化、T 细胞增殖和细胞因子释放情况,从而评估对生物的影响。各种体外细胞检测的结果表明,在细胞检测中,650 微克的降解剂携带量无论是单独存在还是添加到相同或交叉产品中,都不会增加免疫原性风险,这表明目前 650 微克/剂量的清洁诱导降解剂携带量的 PDE 不会对患者产生免疫原性风险。
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Experimental Validation of a Parenteral Permitted Daily Exposure Value for Cleaning-Induced Degradants from Recombinant Therapeutic Proteins with In Vitro Immunogenicity Assays.

Multiproduct manufacturing of biotherapeutic proteins generate cleaning-induced protein degradants because of extreme pH and temperature conditions during the cleaning process. Cleaning Acceptance limits are calculated based on the maximum allowable carryover (MAC) assessment of the previously manufactured active pharmaceutical ingredient (API) - or drug product - based on the permitted daily exposure (PDE) of the previously manufactured API into the dose of subsequent product. In this study, we tested a previously determined PDE value for cleaning-induced protein degradants of 650 µg/dose. A bench-scale cleaning method was used to generate cleaning induced degradants from both a half-life extension (HLE) BiTE® molecule and a mAb product. For this investigation degradants of HLE BiTE®-A and mAb-1 were characterized either alone or degradants of HLE BiTE®-A and mAb-1 spiked into mAb-1 at 650 µg. These samples were characterized by endotoxin testing, size exclusion chromatography (SEC), light obscuration by HIAC, and micro-fluidic imaging (MFI). These results suggest that significant degradation of the molecule occurs because of the cleaning procedure, and it is no longer in the intact form or active state. The biological impact was assessed using a cell line assay to assess immune activation, and a human Peripheral Blood Mononuclear Cell (PBMC) assay to assess T cell activation, T cell proliferation, and cytokine release after 20 hours and 7 days. Findings from the various in vitro cell-based assays suggest that the presence of 650 µg of carryover of degradants either alone or spiked into the same or a cross-product do not increase immunogenicity risk in cell-based assays - suggesting that the current PDE of 650 µg/dose for cleaning-induced degradant carryover does not have a risk of immunogenicity in patients.

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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
期刊介绍: The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.
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