Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy,European Journal of Nuclear Medicine and Molecular Imaging

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Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2022-10-22 , DOI: 10.1007/s00259-022-05968-6
Annie Ogasawara ₁ , James R Kiefer ₂ , Herman Gill ₁ , Eugene Chiang ₃ , Shravan Sriraman ₁ , Gregory Z Ferl ₄ , James Ziai ₅ , Sandra Sanabria Bohorquez ₆ , Sebastian Guelman ₇ , Xiangdan Wang ₇ , Jihong Yang ₇ , Minh Michael Phan ₇ , Van Nguyen ₇ , Shan Chung ₇ , Christine Yu ₂ , Jeff Tinianow ₁ , Stijn Jan Hein Waaijer ₁ , Alex De Crespigny ₆ , Jan Marik ₁ , C Andrew Boswell ₄ , Tanja Zabka ₈ , Karin Staflin ₉ , Simon-Peter Williams ₁

Affiliation

Background

ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1].

Methods

Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function. Immuno-PET with ZED8 was assessed in huCD8⁺ tumor-bearing mice and in non-human primates. Plasma antibody levels were measured by ELISA to determine pharmacokinetic parameters, and OLINDA 1.0 was used to estimate radiation dosimetry from image-derived biodistribution data.

Results

ZED8 selectively binds to human CD8α at a binding site approximately 9 Å from that of MHCI making mutual interference unlikely. The equilibrium dissociation constant (K_D) is 5 nM. ZED8 binds to cynomolgus CD8 with reduced affinity (66 nM) but it has no measurable affinity for rat or mouse CD8. In a series of lymphoma xenografts, ZED8 imaging was able to identify different CD8 levels concordant with flow cytometry. In cynomolgus monkeys with tool compound ⁸⁹Zr-aCD8v17, lymph nodes were conspicuous by imaging 24 h post-injection, and the pharmacokinetics suggested a flat-fixed first-in-human dose of 4 mg per subject. The whole-body effective dose for an adult human was estimated to be 0.48 mSv/MBq, comparable to existing ⁸⁹Zr immuno-PET reagents.

Conclusion

⁸⁹Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy.

中文翻译：

ZED8 的临床前开发，一种 89Zr 免疫 PET 试剂，用于监测接受癌症免疫治疗的患者的肿瘤 CD8 状态

背景

ZED8 是一种新型单价抗体，用锆 89 标记，用于 CD8 的分子成像。这项工作描述了非临床研究，部分目的是为 ZED8 的早期临床开发提供基本原理和告知预期，例如临床试验注册中心 NCT04029181 [1] 中概述的研究。

方法

表面等离子体共振、X 射线晶体学和流式细胞术用于表征 ZED8-CD8 结合相互作用、其特异性及其对 T 细胞功能的影响。在 huCD8 ⁺ 荷瘤小鼠和非人灵长类动物中评估了 ZED8 的免疫 PET。通过 ELISA 测量血浆抗体水平以确定药代动力学参数，并使用 OLINDA 1.0 从图像衍生的生物分布数据估计辐射剂量测定。

结果

ZED8 在距离 MHCI 约 9 Å 的结合位点选择性地结合人 CD8α，因此不太可能相互干扰。平衡解离常数 ( K _D ) 为 5 nM。ZED8 以降低的亲和力 (66 nM) 与食蟹猴 CD8 结合，但它对大鼠或小鼠 CD8 没有可测量的亲和力。在一系列淋巴瘤异种移植物中，ZED8 成像能够识别与流式细胞术一致的不同 CD8 水平。^{在使用工具化合物89} Zr-aCD8v17 的食蟹猴中，注射后 24 小时成像时淋巴结明显，药代动力学表明每个受试者的固定首次人体剂量为 4 mg。成人的全身有效剂量估计为 0.48 mSv/MBq，与现有的⁸⁹ Zr 免疫 PET 试剂相当。