Ceuppens Hannelore, Pombo Antunes Ana Rita, Navarro Laurent, Ertveldt Thomas, Berdal Marion, Nagachinta Surasa, De Ridder Kirsten, Lahoutte Tony, Keyaerts Marleen, Devoogdt Nick, Goyvaerts Cleo, D'Huyvetter Matthias, Breckpot Karine
Vrije Universiteit Brussel, Department of Biomedical Sciences, Translational Oncology Research Center, Laboratory for Molecular and Cellular Therapy, Laarbeeklaan 103. Building E, Brussels, 1090, Belgium.
Precirix NV/SA, Burg. Etienne Demunterlaan 3, Brussels, B-1090, Belgium.
Eur J Nucl Med Mol Imaging. 2025 Jan;52(2):444-457. doi: 10.1007/s00259-024-06914-4. Epub 2024 Sep 6.
Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with Ac or I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB).
We studied the biodistribution and tumour uptake of [I]I-GMIB-4AH29 and [Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [I]I-GMIB-4AH29 and [Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB.
The biodistribution showed high tumour uptake of [I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [I]I-GMIB-4AH29 or [Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy.
[Ac]Ac-DOTA-4AH29 and [I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy.
靶向放射性核素治疗（TRT）是一种对多种癌症类型都具有相对治疗效果的癌症治疗方法。我们在表达人成纤维细胞活化蛋白-α（hFAP）的肺癌小鼠模型中，研究了用锕（Ac）或碘（I）标记的靶向成纤维细胞活化蛋白-α（FAP）的单域抗体（sdAbs，4AH29）在免疫活性小鼠中进行TRT的治疗潜力。我们进一步探索了TRT与程序性细胞死亡配体1（PD-L1）免疫检查点阻断（ICB）的联合应用。
我们通过离体γ计数研究了[I]I-GMIB-4AH29和[Ac]Ac-DOTA-4AH29的生物分布和肿瘤摄取情况。在免疫活性小鼠模型中评估了[I]I-GMIB-4AH29和[Ac]Ac-DOTA-4AH29的治疗效果。对[Ac]Ac-DOTA-4AH29治疗的小鼠的肿瘤进行了流式细胞术分析。重复用[Ac]Ac-DOTA-4AH29联合PD-L1 ICB进行治疗。
生物分布显示，[I]I-GMIB-4AH29在注射后1小时肿瘤摄取率较高，为3.5±0.5%IA/g，24小时后降至0.9±0.1%IA/g。[Ac]Ac-DOTA-4AH29的肿瘤摄取率也较高，注射后1小时为2.1±0.5%IA/g，24小时后下降幅度较小，为1.7±0.2%IA/g。与赋形剂溶液相比，用低剂量和高剂量的[I]I-GMIB-4AH29或[Ac]Ac-DOTA-4AH29治疗后，生存期显著延长。此外，与赋形剂溶液相比，我们观察到用[Ac]Ac-DOTA-4AH29治疗的小鼠肿瘤中PD-L1表达显著更高。因此，我们将高剂量的[Ac]Ac-DOTA-4AH29与PD-L1 ICB联合使用，显示出治疗协同作用。
[Ac]Ac-DOTA-4AH29和[I]I-GMIB-4AH29表现出高且持续的肿瘤靶向性，可使侵袭性肿瘤小鼠的生存期延长。此外，我们证明PD-L1 ICB与[Ac]Ac-DOTA-4AH29 TRT联合可增强其治疗效果。
