Husar Elisabeth, Solonets Maria, Kuhlmann Olaf, Schick Eginhard, Piper-Lepoutre Hanna, Singer Thomas, Tyagi Gaurav
1 Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
2 Safety Science, F. Hoffmann-La Roche, Basel, Switzerland.
Toxicol Pathol. 2017 Jul;45(5):676-686. doi: 10.1177/0192623317723539.
Obinutuzumab (GA101, Gazyva™, Gazyvaro®, F. Hoffmann-La Roche AG, Basel, Switzerland) is a humanized, glycoengineered type II antibody targeted against CD20. The preclinical safety evaluation required to support clinical development and marketing authorization of obinutuzumab included repeat-dose toxicity studies in cynomolgus monkeys for up to 6-month dosing with a 9-month recovery period. Results from those studies showed decreases in circulating B cells and corresponding B-cell depletion in lymphoid tissues, consistent with the desired pharmacology of obinutuzumab. Hypersensitivity reactions were noted at all doses in the 6-month study and were attributed to the foreign recognition of the drug construct in cynomolgus monkeys. Findings in monkeys were classified as acute hypersensitivity reactions that were evident immediately after dosing, such as excessive salivation, erythema, pruritus, irregular respiration, or ataxia, or chronic hypersensitivity reactions characterized by glomerulonephritis, arteritis/periarteritis, and inflammation in several tissues including serosal/adventitial inflammation. Immune complex deposits were demonstrated in tissues by immunohistochemistry, immunofluorescence, and electron microscopy. Some of, but not all, the animals that developed these reactions had detectable antidrug antibodies or circulating immune complexes accompanied by loss of drug exposure and pharmacodynamic effect. On the basis of clinical evidence to date, hypersensitivity reactions following obinutuzumab are rare, further supporting the general view that incidence and manifestation of immunogenicity in nonclinical species are generally not predictive for humans.
奥妥珠单抗（GA101，商品名Gazyva™、Gazyvaro®，瑞士巴塞尔的F. Hoffmann-La Roche AG公司）是一种人源化的、经糖基工程改造的靶向CD20的II型抗体。支持奥妥珠单抗临床开发和上市许可所需的临床前安全性评估包括在食蟹猴中进行长达6个月给药、恢复期为9个月的重复给药毒性研究。这些研究结果显示循环B细胞减少以及淋巴组织中相应的B细胞耗竭，这与奥妥珠单抗预期的药理学作用一致。在6个月的研究中，所有剂量组均观察到超敏反应，这些反应归因于食蟹猴对药物结构的异源识别。在猴子身上观察到的反应分为急性超敏反应，表现为给药后立即出现的明显症状，如流涎过多、红斑、瘙痒、呼吸不规则或共济失调，以及慢性超敏反应，其特征为肾小球肾炎、动脉炎/动脉周围炎以及包括浆膜/外膜炎症在内的多个组织的炎症。通过免疫组织化学、免疫荧光和电子显微镜在组织中证实了免疫复合物沉积。出现这些反应的部分（而非全部）动物可检测到抗药物抗体或循环免疫复合物，并伴有药物暴露和药效学作用的丧失。根据目前的临床证据来看，奥妥珠单抗之后发生的超敏反应较为罕见，这进一步支持了以下普遍观点：非临床物种中免疫原性的发生率和表现通常不能预测人类的情况。
