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.

中文翻译：

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剂量递增PET成像可优化双特异性抗体的安全性和有效治疗剂量。

选择剂量以进行双特异性抗体（BsAbs）的功效和首次人体研究是一个具有挑战性的过程。本文中，使用具有89Zr标记的IBI322（抗CD47 / PD-L1 BsAb）的正电子发射断层扫描（PET）成像来优化安全性和有效治疗剂量。通过用89Zr标记，我们旨在评估携带MC38肿瘤的人源化转基因动物模型（hCD47和hPDL1的敲入）中IBI322与剂量递增动态PET成像的药代动力学（PK），安全性和靶标参与。89锆标记的IBI322在168 h（0.22 mg / kg）时肿瘤与肌肉的比例为12.37±1.42的特异性聚集在肿瘤中，PET成像显示正常组织的生物分布可用于初步安全性预测。根据ELISA定量血清浓度和心脏摄取（％ID / g）之间的Pearson相关分析（r = 0.980），提出了一种改进的Patlak模型。使用当前改良的Patlak模型，计算了探索性靶标介导的50％（0.38 mg / kg）和90％（0.63 mg / kg）抑制质量剂量。初步药效学（PD）研究为0.34 mg / kg，表明剂量预测是合理的。总之，采用89Zr标记抗体的剂量递增PET成像有望用于PK / PD建模和安全性预测，并有助于确定BsAb的临床前和临床试验的合理剂量。初步药效学（PD）研究显示0.34 mg / kg剂量预测是合理的。总之，采用89Zr标记抗体的剂量递增PET成像有望用于PK / PD建模和安全性预测，并有助于确定BsAb的临床前和临床试验的合理剂量。初步药效学（PD）研究显示0.34 mg / kg剂量预测是合理的。总之，采用89Zr标记抗体的剂量递增PET成像有望用于PK / PD建模和安全性预测，并有助于确定BsAb的临床前和临床试验的合理剂量。