High Affinity Promotes Internalization of Engineered Antibodies Targeting FGFR1.
High Affinity Promotes Internalization of Engineered Antibodies Targeting FGFR1.
复制标题
DOI：
10.3390/ijms19051435
复制
发表时间：
2018-05-10
影响因子：
5.6
通讯作者：
Otlewski J
中科院分区：
文献类型：
--
作者：
Opaliński Ł;Szymczyk J;Szczepara M;Kucińska M;Krowarsch D;Zakrzewska M;Otlewski J
成纤维细胞生长因子受体1（FGFR 1）是一种质膜蛋白，其从细胞外环境传递信号，调节细胞稳态和功能。FGFR 1的失调导致人类癌症和非癌性疾病的发展。许多肿瘤过度产生FGFR 1，使该受体成为癌症治疗的潜在靶点。抗体-药物缀合物（ADC）是高效和选择性的抗癌剂。ADC由融合到高细胞毒性药物（弹头）的抗体（靶向因子）组成。ADC策略的效率很大程度上取决于细胞毒性缀合物内化到癌细胞中。在这里，我们研究了抗FGFR 1抗体的亲和力与其细胞摄取效率之间的相互作用。我们已经开发了一组独特的工程化抗FGFR 1抗体，其结合FGFR 1的细胞外部分中的相同表位，但具有不同的亲和力。我们已经证明这些抗体以FGFR 1依赖性方式被癌细胞有效摄取。有趣的是，我们发现定义为抗体内化速率和水平的效率在很大程度上取决于工程化抗体对FGFR 1的亲和力，因为高亲和力抗体显示出最快的内化动力学。我们的数据可能有助于设计治疗相关的靶向分子，用于选择性治疗FGFR 1过度产生的癌症。
Fibroblast growth factor receptor 1 (FGFR1) is a plasma membrane protein that transmits signals from the extracellular environment, regulating cell homeostasis and function. Dysregulation of FGFR1 leads to the development of human cancers and noncancerous diseases. Numerous tumors overproduce FGFR1, making this receptor a perspective target for cancer therapies. Antibody-drug conjugates (ADCs) are highly potent and selective anticancer agents. ADCs are composed of antibodies (targeting factors) fused to highly cytotoxic drugs (warheads). The efficiency of ADC strategy largely depends on the internalization of cytotoxic conjugate into cancer cells. Here, we have studied an interplay between affinity of anti-FGFR1 antibodies and efficiency of their cellular uptake. We have developed a unique set of engineered anti-FGFR1 antibodies that bind the same epitope in the extracellular part of FGFR1, but with different affinities. We have demonstrated that these antibodies are effectively taken up by cancer cells in the FGFR1-dependent manner. Interestingly, we have found that efficiency, defined as rate and level of antibody internalization, largely depends on the affinity of engineered antibodies towards FGFR1, as high affinity antibody displays fastest internalization kinetics. Our data may facilitate design of therapeutically relevant targeting molecules for selective treatment of FGFR1 overproducing cancers.
登录
查看更多内容
DOI：
10.1186/s13046-017-0667-1
发表时间：
2018-02-06
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chalouni C;Doll S
通讯作者：
Doll S
影响因子：
5.8
作者：
Schmidt, Michael M.;Thurber, Greg M.;Wittrup, K. Dane
通讯作者：
Wittrup, K. Dane
影响因子：
5.2
作者：
Sokolowska-Wedzina, Aleksandra;Chodaczek, Grzegorz;Otlewski, Jacek
通讯作者：
Otlewski, Jacek
影响因子：
4.9
作者：
Glatt, Dylan M.;Vera, Denis R. Beckford;Mumper, Russell J.
通讯作者：
Mumper, Russell J.
影响因子：
4.6
作者：
Opalinski, Lukasz;Sokolowska-Wedzina, Aleksandra;Otlewski, Jacek
通讯作者：
Otlewski, Jacek