Pfizer Worldwide Research and Development, Groton, Connecticut, CT 06340, USA.
J Alzheimers Dis. 2012;28(3):531-41. doi: 10.3233/JAD-2011-110869.
Ponezumab (PF-04360365) is a novel humanized IgG2Δa monoclonal antibody that binds to amyloid-β (Aβ). It is designed to have reduced immune effector function compared to other passive immunotherapies for Alzheimer's disease (AD). Toxicity was evaluated in cynomolgus monkeys treated intravenously with vehicle or 10, 30, or 100 mg/kg of ponezumab every 10th day for up to 39 weeks, and after a 12-week recovery phase. The Aβ peptide sequence of monkeys is identical to that of humans. No substantial difference in test article exposure between sexes was observed, and mean plasma Cmax and AUC0-n were approximately dose-proportional. Ponezumab was detectable approximately 9 weeks after cessation of dosing. All animals, except two males given 10 mg/kg, maintained exposure to test article. One of these males tested positive for anti-ponezumab antibodies. Ponezumab was detected in the cerebrospinal fluid (CSF) of animals given active treatment. The estimated CSF/plasma ponezumab concentration ratio was <0.008 after multiple doses. At the end of the dosing and recovery phases, plasma Aβ1-40 and Aβ1-x were increased in treated animals versus controls. No test article-related effects were seen after ophthalmogical, cardiovascular, physical examinations, and clinical and anatomic pathology evaluations. Plasma concentrations of ponezumab on day 261 at the no observed adverse effect level of 100 mg/kg were 22.4 and 5.3 times greater on a Cmax and AUC basis, respectively, than human exposures at the highest dose (10 mg/kg) in a single-dose Phase I trial. These data suggest an acceptable safety profile for ponezumab as an immunotherapy for AD.
蓬奈珠单抗（PF-04360365）是一种新型人源化 IgG2Δa 单克隆抗体，可与淀粉样蛋白-β（Aβ）结合。与其他用于治疗阿尔茨海默病（AD）的被动免疫疗法相比，它旨在降低免疫效应功能。在静脉注射用载体或 10、30 或 100mg/kg 蓬奈珠单抗治疗的食蟹猴中评估了毒性，每 10 天给药一次，共 39 周，然后进行 12 周恢复期。猴子的 Aβ 肽序列与人相同。未观察到雌雄间受试物暴露存在实质性差异，且平均血浆 Cmax 和 AUC0-n 约呈剂量比例关系。停药后约 9 周可检测到蓬奈珠单抗。除了 10mg/kg 组的两只雄性动物外，所有动物均维持对受试物的暴露。其中一只雄性动物抗蓬奈珠单抗抗体检测呈阳性。在接受活性治疗的动物的脑脊液（CSF）中检测到蓬奈珠单抗。多次给药后 CSF 与血浆的蓬奈珠单抗浓度比<0.008。在给药和恢复期结束时，与对照组相比，治疗动物的血浆 Aβ1-40 和 Aβ1-x 增加。在眼科、心血管、体检以及临床和解剖病理学评估后，未观察到与受试物相关的影响。在剂量和恢复期结束时，100mg/kg 无观察到不良效应水平下，蓬奈珠单抗在第 261 天的血浆浓度在 Cmax 和 AUC 上分别比单次给药 I 期临床试验中最高剂量（10mg/kg）的人体暴露高 22.4 和 5.3 倍。这些数据表明，蓬奈珠单抗作为 AD 的免疫疗法具有可接受的安全性特征。
