Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers

被引：53

作者：

Pillow, Thomas H. ^{[1
]}

Schutten, Melissa ^{[1
]}

Yu, Shang-Fan ^{[1
]}

Ohri, Rachana ^{[1
]}

Sadowsky, Jack ^{[1
]}

Poon, Kirsten Achilles ^{[1
,4
]}

Solis, Willy ^{[1
,5
]}

Zhong, Fiona ^{[1
]}

Del Rosario, Geoffrey ^{[1
]}

Go, Mary Ann T. ^{[1
]}

Lau, Jeffrey ^{[1
]}

Yee, Sharon ^{[1
]}

He, Jintang ^{[1
]}

Liu, Luna ^{[1
]}

Ng, Carl ^{[1
]}

Xu, Keyang ^{[1
]}

Leipold, Douglas D. ^{[1
]}

Kamath, Amrita V. ^{[1
]}

Zhang, Donglu ^{[1
]}

Masterson, Luke ^{[2
]}

Gregson, Stephen J. ^{[2
]}

Howard, Philip W. ^{[2
]}

Fang, Fan ^{[3
]}

Chen, Jinhua ^{[3
]}

Gunzner-Toste, Janet ^{[1
]}

Kozak, Katherine K. ^{[1
]}

Spencer, Susan ^{[1
]}

Polakis, Paul ^{[1
]}

Polson, Andrew G. ^{[1
]}

Flygare, John A. ^{[1
]}

Junutula, Jagath R. ^{[1
,6
]}

机构：

[1] Genentech Inc, San Francisco, CA 94030 USA

[2] Spirogen Ltd, QMBInnovat Ctr, London, England

[3] WuXi AppTec Co Ltd, Shanghai, Peoples R China

[4] Denali Therapeut, San Francisco, CA USA

[5] Bristol Myers Squibb, Princeton, NJ USA

[6] Cellerant Therapeut, San Carlos, CA USA

来源：

MOLECULAR CANCER THERAPEUTICS | 2017年 / 16卷 / 05期

关键词：

BIOLOGICAL EVALUATION; TARGETED TREATMENT; CANCER-THERAPY; IN-VIVO; DESIGN; CHEMISTRY; SELECTION; STABILITY; LYMPHOMA; DELIVERY;

D O I：

10.1158/1535-7163.MCT-16-0641

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody-drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. (C) 2017 AACR.

引用

页码：871 / 878

页数：8

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