Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody
Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody
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剂量递增 PET 成像可实现双特异性抗体的安全性和有效治疗剂量优化
DOI：
10.1080/19420862.2020.1748322
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发表时间：
2020-01-01
期刊：
影响因子：
5.3
通讯作者：
Miao, Liyan
中科院分区：
文献类型：
--
作者：
Wang, Yan;Pan, Donghui;Miao, Liyan
选择双特异性抗体（BsAbs）的有效剂量和首次人体研究是一个具有挑战性的过程。本研究使用89zr标记的抗cd47 /PD-L1 BsAb IBI322进行正电子发射断层扫描（PET）成像，以优化安全性和有效治疗剂量。通过89Zr标记，我们旨在通过剂量递增动态PET成像评估IBI322在携带MC38肿瘤（hCD47和hPDL1敲入）的人源化转基因动物模型中的药代动力学（PK）、安全性和靶向性。89zr标记的IBI322在肿瘤中特异性积累，168 h （0.22 mg/kg）时肿瘤与肌肉的比值为12.37±1.42，PET成像正常组织的生物分布可用于初步安全性预测。根据elisa定量血清浓度与心脏摄取（%ID/g）之间的Pearson相关性分析（r = 0.980），提出改进的Patlak模型。探索性目标介导的50% （0.38 mg/kg）和90% （0.63 mg/kg）抑制质量剂量用当前改进的Patlak模型计算。初步的药效学研究表明，0.34 mg/kg的剂量预测是合理的。综上所述，使用89zr标记的抗体进行剂量递增PET成像，有望用于PK/PD建模和安全性预测，并有助于确定bsab临床前和临床试验的合理剂量。
ABSTRACT Selecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89Zr, we aimed to assess the pharmacokinetics (PK), safety, and target engagement of IBI322 with dose escalation dynamic PET imaging in humanized transgenic animal models bearing MC38 tumors (knock-in of hCD47 and hPDL1). 89Zr-labeled IBI322 specifically accumulated in tumors with a tumor-to-muscle ratio of 12.37 ± 1.42 at 168 h (0.22 mg/kg) and the biodistribution of normal tissues from PET imaging could be used for preliminary safety prediction. According to the Pearson correlation analysis between the ELISA-quantified serum concentration and heart uptake (%ID/g) (r = 0.980), a modified Patlak model was proposed. The exploratory target-mediated 50% (0.38 mg/kg) and 90% (0.63 mg/kg) inhibitory mass doses were calculated with the current modified Patlak model. The preliminary pharmacodynamics (PD) study with 0.34 mg/kg revealed that the dose prediction was rational. In conclusion, dose escalation PET imaging with 89Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs.