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

Yanming Wang,Lianqi Liu,Xinbo Zhou,Shiyong Fan,Fei Xie,Dian Xiao,Wu Zhong,Wei Li

doi:10.3390/cancers12030744

Abstract

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.

Highlights

Antibody-drug conjugates (ADCs), using antibodies to selectively deliver potent cytotoxins to tumor cells, have recently become a promising next-generation of anticancer drugs [1,2]
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Summary

Introduction

Antibody-drug conjugates (ADCs), using antibodies to selectively deliver potent cytotoxins to tumor cells, have recently become a promising next-generation of anticancer drugs [1,2]. Monomethyl auristatin E (MMAE), a synthetic analog of dolastatin 10 with high potency at the cellular level (IC50 : 10−11 –10−9 M) [6,7], is the most commonly used cytotoxins in nearly one-third of clinical ADCs [1,8]. The valine-citrulline (VC) dipeptide-based and glucuronides-based cleavable linker systems rely on 1,6-elimination of spacers to drive the release of free MMAE (Figure S1) [10]. At present, this self-immolative cleavable linker system has been successfully applied to the marketed ADCs such as

Methods

Discussion

Conclusion