Paris-Saclay University, CEA, CNRS, Inserm, BioMaps, Service Hospitalier Frédéric Joliot, Orsay France.
Paris-Saclay University, CEA, INRAE, Medicines and Healthcare Technologies Department, SIMoS, Gif-sur-Yvette, France.
Theranostics. 2023 Oct 16;13(15):5584-5596. doi: 10.7150/thno.87168. eCollection 2023.
The passage of antibodies through the blood-brain barrier (BBB) and the blood-tumoral barrier (BTB) is determinant not only to increase the immune checkpoint inhibitors efficacy but also to monitor prognostic and predictive biomarkers such as the programmed death ligand 1 (PD-L1) via immunoPET. Although the involvement of neonatal Fc receptor (FcRn) in antibody distribution has been demonstrated, its function at the BBB remains controversial, while it is unknown at the BTB. In this context, we assessed FcRn's role by pharmacokinetic immunoPET imaging combined with focused ultrasounds (FUS) using unmodified and FcRn low-affinity IgGs targeting PD-L1 in a preclinical orthotopic glioblastoma model. Transcranial FUS were applied over the whole brain in mice shortly before injecting the anti-PD-L1 IgG Zr-DFO-C4 or its FcRn low-affinity mutant Zr-DFO-C4 in a syngeneic glioblastoma murine model (GL261-GFP). Brain uptake was measured from PET scans acquired up to 7 days post-injection. Kinetic modeling was performed to compare the brain kinetics of both C4 formats. FUS efficiently enhanced the delivery of both C4 radioligands in the brain with high reproducibility. Zr-DFO-C4 mean concentrations in the brain reached a significant uptake of 3.75±0.41%ID/cc with FUS against 1.92±0.45%ID/cc without, at 1h post-injection. A substantial and similar entry of both C4 radioligands was observed at a rate of 0.163±0.071 mL/h/g of tissue during 10.4±4.6min. The impaired interaction with FcRn of Zr-DFO-C4 significantly decreased the efflux constant from the healthy brain tissue to plasma compared with non-mutated IgG. Abolishing FcRn interaction allows determining the target engagement related to the specific binding as soon as 12h post-injection. Abolishing Fc-FcRn interaction confers improved kinetic properties to Zr-DFO-C4 for immunoPET imaging. FUS-aided BBB/BTB disruption enables quantitative imaging of PD-L1 expression by glioblastoma tumors within the brain.
抗体通过血脑屏障 (BBB) 和血肿瘤屏障 (BTB) 的转运不仅决定了免疫检查点抑制剂的疗效，而且还可以通过 immunoPET 监测程序性死亡配体 1 (PD-L1) 等预后和预测生物标志物。尽管已经证明了新生儿 Fc 受体 (FcRn) 参与了抗体的分布，但它在 BBB 中的作用仍存在争议，而在 BTB 中则尚不清楚。在这方面，我们通过使用针对 PD-L1 的未修饰和 FcRn 低亲和力 IgG 的药代动力学 immunoPET 成像结合聚焦超声 (FUS) 评估了 FcRn 的作用，在临床前原位胶质母细胞瘤模型中。在注射针对 PD-L1 的 IgG Zr-DFO-C4 或其 FcRn 低亲和力突变体 Zr-DFO-C4 之前不久，在荷瘤同基因胶质母细胞瘤小鼠模型 (GL261-GFP) 中对整个大脑进行经颅 FUS。从注射后最多 7 天的 PET 扫描中测量脑摄取。进行了动力学建模以比较两种 C4 格式的脑动力学。 FUS 可有效增强两种 C4 放射性配体在大脑中的传递，具有高度的可重复性。与未使用 FUS 的情况相比，Zr-DFO-C4 在注射后 1 小时时的脑内平均浓度达到了 3.75±0.41%ID/cc 的显著摄取量。在 10.4±4.6min 期间，两种 C4 放射性配体的大量相似进入速率均为 0.163±0.071mL/h/g 组织。与非突变 IgG 相比，Zr-DFO-C4 与 FcRn 的相互作用受损，显著降低了健康脑组织向血浆的外排常数。消除 FcRn 相互作用可使与特异性结合相关的靶标结合在注射后 12h 内确定。 消除 Fc-FcRn 相互作用为 Zr-DFO-C4 进行 immunoPET 成像提供了更好的动力学特性。FUS 辅助的 BBB/BTB 破坏可实现脑内胶质母细胞瘤肿瘤 PD-L1 表达的定量成像。
