A dual-enzyme cleavable linker for antibody-drug conjugates

被引：23

作者：

Bargh, Jonathan D. ^{[1
]}

Walsh, Stephen J. ^{[1
,2
]}

Ashman, Nicola ^{[1
]}

Isidro-Llobet, Albert ^{[3
]}

Carroll, Jason S. ^{[2
]}

Spring, David R. ^{[1
]}

机构：

[1] Univ Cambridge, Dept Chem, Lensfield Rd, Cambridge CB2 1EW, England

[2] Univ Cambridge, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England

[3] GSK, Gunnels Wood Rd, Stevenage SG1 2NY, Herts, England

来源：

CHEMICAL COMMUNICATIONS | 2021年 / 57卷 / 28期

基金：

英国工程与自然科学研究理事会;

关键词：

Enzymes;

D O I：

10.1039/d1cc00957e

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

A novel enzyme cleavable linker for antibody-drug conjugates is reported. The 3-O-sulfo-beta-galactose linker is cleaved sequentially by two lysosomal enzymes - arylsulfatase A and beta-galactosidase - to release the payload in targeted cells. An alpha-HER2 antibody-drug conjugate synthesised using this highly hydrophilic dual-cleavable linker exhibited excellent cytotoxicity and selectivity.

引用

页码：3457 / 3460

页数：4

共 27 条

[11] Sulfatases: Structure, mechanism, biological activity, inhibition, and synthetic utility [J].

Hanson, SR ;

Best, MD ;

Wong, CH .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2004, 43 (43) :5736-5763

[12] Regioselective modification of unprotected glycosides [J].

Jager, Manuel ;

Minnaard, Adriaan J. .

CHEMICAL COMMUNICATIONS, 2016, 52 (04) :656-664

[13] Development and properties of β-glucuronide linkers for monoclonal antibody-drug conjugates [J].

Jeffrey, SC ;

Andreyka, JB ;

Bernhardt, SX ;

Kissler, KM ;

Kline, T ;

Lenox, JS ;

Moser, RF ;

Nguyen, MT ;

Okeley, NM ;

Stone, IJ ;

Zhang, XQ ;

Senter, PD .

BIOCONJUGATE CHEMISTRY, 2006, 17 (03) :831-840

[14] Minor groove binder antibody conjugates employing a water soluble β-glucuronide linker [J].

Jeffrey, Scott C. ;

Nguyen, Minh T. ;

Moser, Ruth F. ;

Meyer, Damon L. ;

Miyamoto, Jamie B. ;

Senter, Peter D. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (08) :2278-2280

[15] Novel Phosphate Modified Cathepsin B Linkers: Improving Aqueous Solubility and Enhancing Payload Scope of ADCs [J].

Kern, Jeffrey C. ;

Dooney, Deborah ;

Zhang, Rena ;

Liang, Linda ;

Brandish, Philip E. ;

Cheng, Mangeng ;

Feng, Guo ;

Beck, Andrew ;

Bresson, Damien ;

Firdos, Juhi ;

Gately, Dennis ;

Knudsen, Nick ;

Manibusan, Anthony ;

Sun, Ying ;

Garbaccio, Robert M. .

BIOCONJUGATE CHEMISTRY, 2016, 27 (09) :2081-2088

[16] Discovery of Pyrophosphate Diesters as Tunable, Soluble, and Bioorthogonal Linkers for Site-Specific Antibody-Drug Conjugates [J].

Kern, Jeffrey C. ;

Cancilla, Mark ;

Dooney, Deborah ;

Kwasnjuk, Kristen ;

Zhang, Rena ;

Beaumont, Maribel ;

Figueroa, Isabel ;

Hsieh, SuChun ;

Liang, Linda ;

Tomazela, Daniela ;

Zhang, Jeffrey ;

Brandish, Philip E. ;

Palmieri, Anthony ;

Stivers, Peter ;

Cheng, Mangeng ;

Feng, Guo ;

Geda, Prasanthi ;

Shah, Sanjiv ;

Beck, Andrew ;

Bresson, Damien ;

Firdos, Juhi ;

Gately, Dennis ;

Knudsen, Nick ;

Manibusan, Anthony ;

Schultz, Peter G. ;

Sun, Ying ;

Garbaccio, Robert M. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2016, 138 (04) :1430-1445

[17] Development and evaluation of β-galactosidase-sensitive antibody-drug conjugates [J].

Kolodych, Sergii ;

Michel, Chloe ;

Delacroix, Sebastien ;

Koniev, Oleksandr ;

Ehkirch, Anthony ;

Eberova, Jitka ;

Cianferani, Sarah ;

Renoux, Brigitte ;

Krezel, Wojciech ;

Poinot, Pauline ;

Muller, Christian D. ;

Papot, Sebastien ;

Wagner, Alain .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2017, 142 :376-382

[18] Crystal structure of human arylsulfatase A: The aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis [J].

Lukatela, G ;

Krauss, N ;

Theis, K ;

Selmer, T ;

Gieselmann, V ;

von Figura, K ;

Saenger, W .

BIOCHEMISTRY, 1998, 37 (11) :3654-3664

[19]

Nejadmoghaddam Mohammad-Reza, 2019, Avicenna Journal of Medical Biotechnology, V11, P3

[20]

Nolting B, 2013, METHODS MOL BIOL, V1045, P71, DOI 10.1007/978-1-62703-541-5_5

← 1 2 3 →