Anti-human PD-L1 Nanobody for Immuno-PET Imaging: Validation of a Conjugation Strategy for Clinical Translation.
Anti-human PD-L1 Nanobody for Immuno-PET Imaging: Validation of a Conjugation Strategy for Clinical Translation.
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DOI：
10.3390/biom10101388
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发表时间：
2020-09-29
期刊：
影响因子：
5.5
通讯作者：
Xavier C
中科院分区：
文献类型：
--
作者：
Bridoux J;Broos K;Lecocq Q;Debie P;Martin C;Ballet S;Raes G;Neyt S;Vanhove C;Breckpot K;Devoogdt N;Caveliers V;Keyaerts M;Xavier C
免疫检查点，如程序性死亡配体1（PD-L1），限制T细胞功能，肿瘤细胞使用这种配体来逃避抗肿瘤免疫反应。用单克隆抗体阻断这些检查点的治疗已经显示出持久的反应，但仅在一部分患者中。本研究旨在开发一种基于纳米抗体（Nb）的探针，以便使用正电子发射断层扫描成像评估人PD-L1（hPD-L1）表达，并比较两种不同放射性标记策略的影响，因为Nb在其互补决定区（CDR）中具有赖氨酸，这可能影响其功能化后的亲和力。Nb已经通过分选酶-A酶与NOTA螯合剂位点特异性地缀合或随机地在其赖氨酸上缀合。获得放射化学纯度>95%的[68 Ga]Ga-NOTA-（hPD-L1）Nbs。注射后1小时20分的体内肿瘤靶向研究显示，位点特异性缀合物的特异性肿瘤摄取为1.89 ± 0.40%IA/g，随机缀合物的特异性肿瘤摄取为1.77 ± 0.29%IA/g，无非特异性器官靶向，并通过肾脏和膀胱排泄。两种策略都允许以高产率容易地获得68 Ga标记的hPD-L1 Nbs。两种缀合物是稳定的，并且显示出优异的体内靶向。此外，我们证明了随机赖氨酸缀合是hPD-L1 Nb临床翻译的有效策略，尽管CDR中存在赖氨酸。
Immune checkpoints, such as programmed death-ligand 1 (PD-L1), limit T-cell function and tumor cells use this ligand to escape the anti-tumor immune response. Treatments with monoclonal antibodies blocking these checkpoints have shown long-lasting responses, but only in a subset of patients. This study aims to develop a Nanobody (Nb)-based probe in order to assess human PD-L1 (hPD-L1) expression using positron emission tomography imaging, and to compare the influence of two different radiolabeling strategies, since the Nb has a lysine in its complementarity determining region (CDR), which may impact its affinity upon functionalization. The Nb has been conjugated with the NOTA chelator site-specifically via the Sortase-A enzyme or randomly on its lysines. [68Ga]Ga-NOTA-(hPD-L1) Nbs were obtained in >95% radiochemical purity. In vivo tumor targeting studies at 1 h 20 post-injection revealed specific tumor uptake of 1.89 ± 0.40%IA/g for the site-specific conjugate, 1.77 ± 0.29%IA/g for the random conjugate, no nonspecific organ targeting, and excretion via the kidneys and bladder. Both strategies allowed for easily obtaining 68Ga-labeled hPD-L1 Nbs in high yields. The two conjugates were stable and showed excellent in vivo targeting. Moreover, we proved that the random lysine-conjugation is a valid strategy for clinical translation of the hPD-L1 Nb, despite the lysine present in the CDR.
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影响因子：
50.5
作者：
Ilie, M.;Long-Mira, E.;Hofman, P.
通讯作者：
Hofman, P.
DOI：
10.1097/pai.0000000000000531
发表时间：
2018-02-01
影响因子：
1.6
作者：
Parra, Edwin R.;Villalobos, Pamela;Rodriguez-Canales, Jaime
通讯作者：
Rodriguez-Canales, Jaime
DOI：
10.1007/978-1-4939-8648-4_26
发表时间：
2018-01-01
期刊：
ANTIBODY ENGINEERING, 3 EDITION
影响因子：
--
作者：
Crauwels, Maxine;Massa, Sam;Muyldermans, Serge
通讯作者：
Muyldermans, Serge
影响因子：
20.4
作者：
Matter-Walstra, Klazien;Schwenkglenks, Matthias;Gautschi, Oliver
通讯作者：
Gautschi, Oliver
影响因子：
9.3
作者：
Donnelly, David J.;Smith, R. Adam;Hayes, Wendy
通讯作者：
Hayes, Wendy