Location Matters: Site of Conjugation Modulates Stability and Pharmacokinetics of Antibody Drug Conjugates

被引：368

作者：

Strop, Pavel ^{[1
]}

Liu, Shu-Hui ^{[1
]}

Dorywalska, Magdalena ^{[1
]}

Delaria, Kathy ^{[1
]}

Dushin, Russell G. ^{[2
]}

Tran, Thomas-Toan ^{[1
]}

Ho, Wei-Hsien ^{[1
]}

Farias, Santiago ^{[1
]}

Casas, Meritxell Galindo ^{[1
]}

Abdiche, Yasmina ^{[1
]}

Zhou, Dahui ^{[2
]}

Chandrasekaran, Ramalakshmi ^{[2
]}

Samain, Caroline ^{[1
]}

Loo, Carole ^{[1
]}

Rossi, Andrea ^{[1
]}

Rickert, Mathias ^{[1
]}

Krimm, Stellanie ^{[1
]}

Wong, Teresa ^{[1
]}

Chin, Sherman Michael ^{[1
]}

Yu, Jessica ^{[1
]}

Dilley, Jeanette ^{[1
]}

Chaparro-Riggers, Javier ^{[1
]}

Filzen, Gary F. ^{[2
]}

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

Wang, Fang ^{[3
]}

Myers, Jeremy S. ^{[3
]}

Pons, Jaume ^{[1
]}

Shelton, David L. ^{[1
]}

Rajpal, Arvind ^{[1
]}

机构：

[1] Rinat Pfizer, San Francisco, CA 94080 USA

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

[3] Pfizer, Oncol Res Unit, Pearl River, NY 10965 USA

来源：

CHEMISTRY & BIOLOGY | 2013年 / 20卷 / 02期

关键词：

LIGHT-CHAIN ANTIBODIES; SUBSTRATE SPECIFICITIES; ANTITUMOR-ACTIVITY;

D O I：

10.1016/j.chembiol.2013.01.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Antibody drug conjugates (ADCs) are a therapeutic class offering promise for cancer therapy. The attachment of cytotoxic drugs to antibodies can result in an effective therapy with better safety potential than nontargeted cytotoxics. To understand the role of conjugation site, we developed an enzymatic method for site-specific antibody drug conjugation using microbial transglutaminase. This allowed us to attach diverse compounds at multiple positions and investigate how the site influences stability, toxicity, and efficacy. We show that the conjugation site has significant impact on ADC stability and pharmacokinetics in a species-dependent manner. These differences can be directly attributed to the position of the linkage rather than the chemical instability, as was observed with a maleimide linkage. With this method, it is possible to produce homogeneous ADCs and tune their properties to maximize the therapeutic window.

引用

页码：161 / 167

页数：7

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