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Impact of Ligand Size and Conjugation Chemistry on the Performance of Universal Chimeric Antigen Receptor T-Cells for Tumor Killing.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-06-09 , DOI: 10.1021/acs.bioconjchem.0c00258 Christian Pellegrino 1 , Nicholas Favalli 1 , Michael Sandholzer 1 , Laura Volta 1 , Gabriele Bassi 1 , Jacopo Millul 2 , Samuele Cazzamalli 2 , Mattia Matasci 2 , Alessandra Villa 2 , Renier Myburgh 3 , Markus G Manz 3 , Dario Neri 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-06-09 , DOI: 10.1021/acs.bioconjchem.0c00258 Christian Pellegrino 1 , Nicholas Favalli 1 , Michael Sandholzer 1 , Laura Volta 1 , Gabriele Bassi 1 , Jacopo Millul 2 , Samuele Cazzamalli 2 , Mattia Matasci 2 , Alessandra Villa 2 , Renier Myburgh 3 , Markus G Manz 3 , Dario Neri 1
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All Universal Chimeric Antigen Receptor T-cells (UniCAR T-cells) are T-cells which have been engineered to recognize a haptenated ligand. Due to this feature, UniCAR T-cells have the potential to mediate a potent and selective tumor killing only in the presence of a haptenated tumor ligand, thus avoiding the long-lasting biocidal effects of conventional CAR T-cells. We have used fluorescein-labeled versions of small organic ligands and different antibody formats specific to carbonic anhydrase IX (a tumor-associated antigen) in order to assess whether the killing potential of UniCAR T-cells depended on the molecular features of the haptenated molecule. Both small molecule ligands and larger antibody fragments were potent in mediating tumor cell killing over a broad concentration range. Antibodies could be conveniently used both in IgG format and as smaller diabody fragments. Importantly, the use of site-specific chemical modification strategies for the antibody coupling to fluorescein led to a substantial improvement of tumor cell killing performance, compared to the random modification of primary amino groups on the antibody surface.
中文翻译：
配体大小和缀合化学对通用嵌合抗原受体T细胞杀伤肿瘤的性能的影响。
所有通用嵌合抗原受体T细胞（UniCAR T细胞）都是经过改造可识别半抗原配体的T细胞。由于此功能，UniCAR T细胞仅在存在半抗原连接的肿瘤配体的情况下才有可能介导有效的选择性肿瘤杀伤，从而避免了常规CAR T细胞的持久杀生物作用。为了评估UniCAR T细胞的杀伤潜力是否取决于半抗原分子的分子特征，我们使用了荧光素标记的小有机配体形式和特定于碳酸酐酶IX（与肿瘤相关的抗原）的不同抗体形式。小分子配体和较大的抗体片段均能在很宽的浓度范围内介导肿瘤细胞的杀伤。抗体可以以IgG形式和较小的双抗体片段方便地使用。重要的是，与抗体表面伯氨基的随机修饰相比，使用位点特异性化学修饰策略使抗体与荧光素偶联导致肿瘤细胞杀伤性能的显着改善。
更新日期：2020-07-15
中文翻译：
配体大小和缀合化学对通用嵌合抗原受体T细胞杀伤肿瘤的性能的影响。
所有通用嵌合抗原受体T细胞（UniCAR T细胞）都是经过改造可识别半抗原配体的T细胞。由于此功能，UniCAR T细胞仅在存在半抗原连接的肿瘤配体的情况下才有可能介导有效的选择性肿瘤杀伤，从而避免了常规CAR T细胞的持久杀生物作用。为了评估UniCAR T细胞的杀伤潜力是否取决于半抗原分子的分子特征，我们使用了荧光素标记的小有机配体形式和特定于碳酸酐酶IX（与肿瘤相关的抗原）的不同抗体形式。小分子配体和较大的抗体片段均能在很宽的浓度范围内介导肿瘤细胞的杀伤。抗体可以以IgG形式和较小的双抗体片段方便地使用。重要的是，与抗体表面伯氨基的随机修饰相比，使用位点特异性化学修饰策略使抗体与荧光素偶联导致肿瘤细胞杀伤性能的显着改善。
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