Fcγ Receptor-Dependent Internalization and Off-Target Cytotoxicity of Antibody-Drug Conjugate Aggregates.
Fcγ Receptor-Dependent Internalization and Off-Target Cytotoxicity of Antibody-Drug Conjugate Aggregates.
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DOI：
10.1007/s11095-021-03158-x
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发表时间：
2022-01
影响因子：
3.7
通讯作者：
Ishii-Watabe A
中科院分区：
文献类型：
--
作者：
Aoyama M;Tada M;Yokoo H;Demizu Y;Ishii-Watabe A
抗体-药物缀合物（ADC）是与高毒性有效负载缀合的单克隆抗体（mAb），由于根据mAb的功能特异性递送有效负载而实现高肿瘤杀伤功效。另一方面，有效载荷的缀合通常增加mAb的疏水性，导致稳定性降低和聚集增加。认为mAb聚集体具有激活免疫细胞上Fcγ受体（Fcγ R）的潜在风险，并通过Fcγ R内化至细胞中。基于ADC的作用机制，ADC内化到靶阴性细胞中可能导致脱靶毒性。然而，聚集对ADC安全性的影响（包括脱靶细胞毒性）尚不清楚。在这项研究中，我们研究了ADC聚集体在靶阴性细胞中的细胞毒性。ADC聚集体通过搅拌应力或热应力产生。在几种靶阴性细胞系中评价了ADC聚集体的脱靶细胞毒性，并使用报告细胞试验表征了ADC聚集体的Fcγ R活化特性。与非应激ADC相比，ADC的聚集增强了几种靶阴性细胞系中的脱靶细胞毒性。值得注意的是，具有Fcγ R活化特性的ADC聚集体在Fcγ R表达细胞中显示出显著增强的细胞毒性。通过使用Fcγ R阻断抗体或Fc工程化沉默Fc介导的效应子功能，降低了ADC聚集体的Fcγ R介导的脱靶细胞毒性。这些结果表明，Fcγ R在ADC聚集体内化至非靶细胞中起重要作用，并且ADC的聚集增加了脱靶毒性的潜在风险。在线版本包含补充材料，可通过10.1007/s11095-021-03158-x获得。
Antibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific delivery of payloads in accordance with mAbs’ function. On the other hand, the conjugation of payloads often increases the hydrophobicity of mAbs, resulting in reduced stability and increased aggregation. It is considered that mAb aggregates have potential risk for activating Fcγ receptors (FcγRs) on immune cells, and are internalized into cells via FcγRs. Based on the mechanism of action of ADCs, the internalization of ADCs into target-negative cells may cause the off-target toxicity. However, the impacts of aggregation on the safety of ADCs including off-target cytotoxicity have been unclear. In this study, we investigated the cytotoxicity of ADC aggregates in target-negative cells. The ADC aggregates were generated by stirring stress or thermal stress. The off-target cytotoxicity of ADC aggregates was evaluated in several target-negative cell lines, and FcγR-activation properties of ADC aggregates were characterized using a reporter cell assay. Aggregation of ADCs enhanced the off-target cytotoxicity in several target-negative cell lines compared with non-stressed ADCs. Notably, ADC aggregates with FcγR-activation properties showed dramatically enhanced cytotoxicity in FcγR-expressing cells. The FcγR-mediated off-target cytotoxicity of ADC aggregates was reduced by using a FcγR-blocking antibody or Fc-engineering for silencing Fc-mediated effector functions. These results indicated that FcγRs play an important role for internalization of ADC aggregates into non-target cells, and the aggregation of ADCs increases the potential risk for off-target toxicity. The online version contains supplementary material available at 10.1007/s11095-021-03158-x.
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影响因子：
20.3
作者：
Chen, Kan;Nishi, Hiroshi;Mayadas, Tanya N.
通讯作者：
Mayadas, Tanya N.
影响因子：
3.8
作者：
Pardeshi, Neha N.;Qi, Wei;Carpenter, John F.
通讯作者：
Carpenter, John F.
DOI：
10.1074/jbc.m111.330902
发表时间：
2012-07-20
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Joubert MK;Hokom M;Eakin C;Zhou L;Deshpande M;Baker MP;Goletz TJ;Kerwin BA;Chirmule N;Narhi LO;Jawa V
通讯作者：
Jawa V
影响因子：
11.5
作者：
Hamblett, KJ;Senter, PD;Francisco, JA
通讯作者：
Francisco, JA
影响因子：
3.8
作者：
Simmons, Jessica K.;Burke, Patrick J.;Lyon, Robert P.
通讯作者：
Lyon, Robert P.