Molecular Basis of Valine-Citrulline-PABC Linker Instability in Site-Specific ADCs and Its Mitigation by Linker Design

被引：154

作者：

Dorywalska, Magdalena ^{[1
]}

Dushin, Russell ^{[2
]}

Moine, Ludivine ^{[2
]}

Farias, Santiago E. ^{[1
]}

Zhou, Dahui ^{[2
]}

Navaratnam, Thayalan ^{[2
,3
]}

Lui, Victor ^{[1
]}

Hasa-Moreno, Adela ^{[1
]}

Casas, Meritxell Galindo ^{[1
]}

Tran, Thomas-Toan ^{[1
]}

Delaria, Kathy ^{[1
]}

Liu, Shu-Hui ^{[1
]}

Foletti, Davide ^{[1
,4
]}

O'Donnell, Christopher J. ^{[2
]}

Pons, Jaume ^{[1
,5
]}

Shelton, David L. ^{[1
]}

Rajpal, Arvind ^{[1
,6
]}

Strop, Pavel ^{[1
,6
]}

机构：

[1] Pfizer Inc, Rinat Labs, San Francisco, CA USA

[2] Pfizer Inc, Worldwide Med Chem, Groton, CT 06340 USA

[3] Toronto Res Chem, 2 Brisbane Rd, Toronto, ON M3J 2J8, Canada

[4] 23andMe, 899 W Evelyn Ave, Mountain View, CA USA

[5] Alexo Therapeut, 951 Gateway Blvd Ste 201, San Francisco, CA 94080 USA

[6] Bristol Myers Squibb, 700 Bay Rd Ste A, Redwood City, CA 94063 USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2016年 / 15卷 / 05期

关键词：

PLASMA CARBOXYLESTERASE; CYSTEINE CATHEPSINS; THERAPEUTIC INDEX; CANCER-THERAPY; CATALYTIC-PROPERTIES; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; IN-VITRO; DRUG; STABILITY;

D O I：

10.1158/1535-7163.MCT-15-1004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The degree of stability of antibody-drug linkers in systemic circulation, and the rate of their intracellular processing within target cancer cells are among the key factors determining the efficacy of antibody-drug conjugates (ADC) in vivo. Previous studies demonstrated the susceptibility of cleavable linkers, as well as auristatin-based payloads, to enzymatic cleavage in rodent plasma. Here, we identify Carboxylesterase 1C as the enzyme responsible for the extracellular hydrolysis of valine-citrulline-p-aminocarbamate (VC-PABC)-based linkers in mouse plasma. We further show that the activity of Carboxylesterase 1C towards VC-PABC-based linkers, and consequently the stability of ADCs in mouse plasma, can be effectively modulated by small chemical modifications to the linker. While the introduced modifications can protect the VC-PABC-based linkers from extracellular cleavage, they do not significantly alter the intracellular linker processing by the lysosomal protease Cathepsin B. The distinct substrate preference of the serum Carboxylesterase 1C offers the opportunity to modulate the extracellular stability of cleavable ADCs without diminishing the intracellular payload release required for ADC efficacy. (C) 2016 AACR.

引用

页码：958 / 970

页数：13

共 41 条

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