Next Article in Journal
A Disintegrin and Metalloproteinase 9 (ADAM9) in Advanced Hepatocellular Carcinoma and Their Role as a Biomarker During Hepatocellular Carcinoma Immunotherapy
Previous Article in Journal
Gauging the Impact of Cancer Treatment Modalities on Circulating Tumor Cells (CTCs)
Article

Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety

National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(3), 744; https://doi.org/10.3390/cancers12030744
Received: 2 March 2020 / Revised: 17 March 2020 / Accepted: 19 March 2020 / Published: 21 March 2020
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 L-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 (mil40-15) not only exhibits ideal plasma stability and maintains potent cytotoxicity as MMAE (IC50: 10−11 M), but also shows improved safety with lower bystander toxicity (IC50: 10−9 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. View Full-Text
Keywords: tumor; antibody-drug conjugate; linker; MMAE; Cys-linker-MMAE tumor; antibody-drug conjugate; linker; MMAE; Cys-linker-MMAE
Show Figures

Figure 1

MDPI and ACS Style

Wang, Y.; Liu, L.; Fan, S.; Xiao, D.; Xie, F.; Li, W.; Zhong, W.; Zhou, X. Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety. Cancers 2020, 12, 744. https://doi.org/10.3390/cancers12030744

AMA Style

Wang Y, Liu L, Fan S, Xiao D, Xie F, Li W, Zhong W, Zhou X. Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety. Cancers. 2020; 12(3):744. https://doi.org/10.3390/cancers12030744

Chicago/Turabian Style

Wang, Yanming, Lianqi Liu, Shiyong Fan, Dian Xiao, Fei Xie, Wei Li, Wu Zhong, and Xinbo Zhou. 2020. "Antibody-Drug Conjugate Using Ionized Cys-Linker-MMAE as the Potent Payload Shows Optimal Therapeutic Safety" Cancers 12, no. 3: 744. https://doi.org/10.3390/cancers12030744

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop