Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Thoracic Surgery，Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Immunother Cancer. 2024 Apr 5;12(4):e008794. doi: 10.1136/jitc-2024-008794.
The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells' immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors' immunotherapy landscape.
By immunizing an alpaca with recombinant human PD-L1, three clones of the ariable domain of the eavy chain of eavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([Ga]Ga-NOTA-RW102, [Ga]Ga-NOTA-ABDRW102, [Cu]Cu-NOTA-ABDRW102, and [Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC).
While RW102 has a high binding affinity to PD-L1 with an excellent K value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent K value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different circulation times. In preclinical studies, [Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [Cu]Cu-NOTA-ABDRW102 and [Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies.
We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments.
NCT06165874.
程序性细胞死亡蛋白 1（PD-1）/程序性死亡受体配体 1（PD-L1）轴对癌细胞的免疫逃逸至关重要。针对 PD-1/PD-L1 轴的抗体治疗在各种肿瘤中显示出显著疗效。PD-L1 表达的免疫正电子发射断层扫描（ImmunoPET）成像可能有助于重塑实体瘤的免疫治疗格局。
通过用重组人 PD-L1 免疫羊驼，筛选出 3 种重链仅有抗体（VHH）的重链可变区的克隆，并选择具有高结合亲和力的 RW102 进行进一步研究。ABDRW102 是一种 VHH 衍生物，通过将 RW102 与白蛋白结合物 ABD035 融合进一步构建。基于这两种靶向载体，开发了四种具有不同循环时间的 PD-L1 特异性示踪剂（[Ga]Ga-NOTA-RW102、[Ga]Ga-NOTA-ABDRW102、[Cu]Cu-NOTA-ABDRW102 和 [Zr]Zr-DFO-ABDRW102）。在临床前实体瘤模型中进行了彻底的诊断功效评估，随后在非小细胞肺癌（NSCLC）患者中进行了 [Ga]Ga-NOTA-RW102 的首次人体转化研究。
虽然 RW102 与 PD-L1 具有高结合亲和力，其 K 值为 15.29 pM，但 ABDRW102 同时与人 PD-L1 和人血清白蛋白结合，其 K 值分别为 3.71 pM 和 3.38 pM。来自 RW102 和 ABDRW102 的放射性示踪剂具有不同的循环时间。在临床前研究中，[Ga]Ga-NOTA-RW102 免疫 PET 成像允许特异性的同日注释差异 PD-L1 表达，而 [Cu]Cu-NOTA-ABDRW102 和 [Zr]Zr-DFO-ABDRW102 则能够进行 PD-L1 的纵向可视化。更重要的是，一项初步临床试验表明，[Ga]Ga-NOTA-RW102 免疫 PET 成像在 NSCLC 患者中的安全性和诊断价值，以及其预测 PD-L1 靶向免疫治疗后免疫相关不良事件的潜力。
我们开发并验证了一系列 PD-L1 靶向示踪剂。初步的临床前和临床证据表明，使用 [Ga]Ga-NOTA-RW102 进行免疫 PET 成像在可视化差异 PD-L1 表达、选择接受 PD-L1 靶向免疫治疗的患者以及监测接受 PD-L1 靶向治疗的患者的免疫相关不良事件方面具有潜力。
NCT06165874。
