PET imaging of programmed cell death ligand 1 (PD-L1) may help to noninvasively predict and monitor responses to anti–programmed cell death 1/anti-PD-L1 immunotherapies. In this study, we compared the imaging characteristics of 3 radioligands derived from the anti-PD-L1 IgG1 complement 4 (C4). In addition to the IgG C4, we produced a fragment antigen-binding (Fab) C4, as well as a double-mutant IgG C4 (H310A/H435Q) with minimal affinity for the murine neonatal Fc receptor. Methods: The pharmacokinetics, biodistribution, and dosimetry of the 3 ⁸⁹Zr-labeled C4 ligands were compared by longitudinal PET/CT imaging in nude mice bearing subcutaneous human non–small cell lung cancer xenografts with positive (H1975 model) or negative (A549 model) endogenous PD-L1 expression. Results: The C4 radioligands substantially accumulated in PD-L1–positive tumors but not in PD-L1–negative tumors or in blocked PD-L1–positive tumors, confirming their PD-L1–specific tumor targeting. ⁸⁹Zr-Fab C4 and ⁸⁹Zr-IgG C4 (H310A/H435Q) were rapidly eliminated compared with ⁸⁹Zr-IgG C4. Consequently, maximal tumor-to-muscle ratios were obtained earlier, at 4 h after injection for ⁸⁹Zr-Fab C4 (ratio, ~6) and 24 h after injection for ⁸⁹Zr-IgG C4 (H310A/H435Q) (ratio, ~9), versus 48 h after injection for ⁸⁹Zr-IgG C4 (ratio, ~8). Background activity in nontumor tissues was low, except for high kidney retention of ⁸⁹Zr-Fab C4 and persistent liver accumulation of ⁸⁹Zr-IgG C4 (H310A/H435Q) compared with ⁸⁹Zr-IgG C4. Dosimetry estimates suggested that the C4 radioligands would yield organ-absorbed doses tolerable for repeated clinical PET imaging studies. Conclusion: This study highlights the potential of designing radioligands with shorter pharmacokinetics for PD-L1 immuno-PET imaging in a preclinical model and encourages further clinical translation of such radioligands.

程序性细胞死亡配体 1 (PD-L1) 的 PET 成像可能有助于无创预测和监测对抗程序性细胞死亡 1/抗 PD-L1 免疫疗法的反应。在这项研究中，我们比较了源自抗 PD-L1 IgG1 补体 4 (C4) 的 3 种放射性配体的成像特征。除了 IgG C4，我们还生产了一个片段抗原结合 (Fab) C4，以及一个对小鼠新生儿 Fc 受体具有最小亲和力的双突变 IgG C4 (H310A/H435Q)。方法：通过纵向 PET/CT 成像在带有阳性（H1975 模型）或阴性（A549 模型）皮下人非小细胞肺癌异种移植物的裸鼠中比较3 ⁸⁹ Zr 标记的 C4 配体的药代动力学、生物分布和剂量学。) 内源性 PD-L1 表达。结果： C4 放射性配体在 PD-L1 阳性肿瘤中大量积累，但在 PD-L1 阴性肿瘤或阻断的 PD-L1 阳性肿瘤中没有积累，证实了它们的 PD-L1 特异性肿瘤靶向。^{与89 Zr-IgG C4 相比， 89} Zr-Fab C4 和⁸⁹ Zr-IgG C4 (H310A/H435Q) 被快速消除。因此，在注射⁸⁹ Zr-Fab C4 后 4 小时（比率，~6）和注射⁸⁹ Zr-IgG C4（H310A/H435Q）后 24 小时（比率，~ 9），与注射⁸⁹ Zr-IgG C4后 48 小时相比（比率，~8）。非肿瘤组织中的背景活性低，除了高肾潴留^89与89 Zr-IgG C4 相比， Zr-Fab C4 和⁸⁹ Zr-IgG C4 (H310A/H435Q)的持续肝脏积累。剂量学估计表明，C4 放射性配体将产生重复临床 PET 成像研究可耐受的器官吸收剂量。结论：本研究强调了在临床前模型中设计用于 PD-L1 免疫 PET 成像的药代动力学较短的放射性配体的潜力，并鼓励此类放射性配体的进一步临床转化。