Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety
Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities...
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/3/744 |
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| author | Yanming Wang Lianqi Liu Shiyong Fan Dian Xiao Fei Xie Wei Li Wu Zhong Xinbo Zhou |
| author_facet | Yanming Wang Lianqi Liu Shiyong Fan Dian Xiao Fei Xie Wei Li Wu Zhong Xinbo Zhou |
| author_sort | Yanming Wang |
| collection | DOAJ |
| description | Monomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized <i>L</i>-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-<b>15</b>) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC<sub>50</sub>: 10<sup>−11</sup> M), but also shows improved safety with lower bystander toxicity (IC<sub>50</sub>: 10<sup>−9</sup> M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs. |
| first_indexed | 2024-03-12T04:40:04Z |
| format | Article |
| id | doaj.art-7374f5d3d4084c8cbd4602030859a5b5 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T04:40:04Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7374f5d3d4084c8cbd4602030859a5b52023-09-03T09:44:13ZengMDPI AGCancers2072-66942020-03-0112374410.3390/cancers12030744cancers12030744Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic SafetyYanming Wang0Lianqi Liu1Shiyong Fan2Dian Xiao3Fei Xie4Wei Li5Wu Zhong6Xinbo Zhou7National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaNational Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, ChinaMonomethyl auristatin E (MMAE) is the most popular and widely used cytotoxin in the development of antibody-drug conjugates (ADCs). However, current MMAE-based ADCs are all constructed using cleavable linkers, and this design concept still has insurmountable drawbacks. Their potential instabilities and lipophilic MMAE-induced “bystander effect” inevitably increase the toxicity to normal tissues. Herein, we overturn previous negative views of MMAE-based ADCs with non-cleavable linkers and propose using ionized <i>L</i>-Cysteine (Cys)-linker-MMAE as a novel payload, which can ingeniously enrich and enter tumor cells through receptor-mediated endocytosis of antibodies while its lower permeability helps to avoid further off-target toxicity. We demonstrate that Cys-linker-MMAE maintains high potency similar to free MMAE at the tubulin molecular level and can also be efficiently released in target cells. As a result, the preferred ADC (mil40-<b>15</b>) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC<sub>50</sub>: 10<sup>−11</sup> M), but also shows improved safety with lower bystander toxicity (IC<sub>50</sub>: 10<sup>−9</sup> M), its maximum tolerated dose approaching the level of the naked antibody (160 mg/kg). This study indicated that Cys-linker-MMAE has the potential as a potent payload for ADCs, which is expected to provide novel strategies for the development of MMAE-based ADCs.https://www.mdpi.com/2072-6694/12/3/744tumorantibody-drug conjugatelinkermmaecys-linker-mmae |
| spellingShingle | Yanming Wang Lianqi Liu Shiyong Fan Dian Xiao Fei Xie Wei Li Wu Zhong Xinbo Zhou Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety Cancers tumor antibody-drug conjugate linker mmae cys-linker-mmae |
| title | Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety |
| title_full | Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety |
| title_fullStr | Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety |
| title_full_unstemmed | Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety |
| title_short | Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety |
| title_sort | antibody drug conjugate using ionized cys linker mmae as the potent payload shows optimal therapeutic safety |
| topic | tumor antibody-drug conjugate linker mmae cys-linker-mmae |
| url | https://www.mdpi.com/2072-6694/12/3/744 |
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