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

共 50 条

[31] Evaluation of Double Self-Immolative Linker-Based Antibody-Drug Conjugate FDA022-BB05 with Enhanced Therapeutic Potential
Zhang, Yifan
Wang, Lei
Cao, Xuemei
Song, Ruiwen
Yin, Sicheng
Cheng, Zhiyang
Li, Weinan
Shen, Keyu
Zhao, Teng
Xu, Jun
Liu, Shuangxi
Xie, Qian
Wu, Yinghan
Gao, Bei
Guo, Qingsong
Wu, Jingsong
Qiu, Xuefei
Wang, Baoxia
Zhang, Wenbo
Yang, Tong
Lu, Wei
Zhu, Shulei
JOURNAL OF MEDICINAL CHEMISTRY, 2024, 67 (21) : 19852 - 19873
[32] Therapeutic index improvement of antibody-drug conjugates
Gerber, Hans-Peter
Gangwar, Sanjeev
Betts, Alison
MABS, 2023, 15 (01)
[33] Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates
Gebleux, Remy
Wulhfard, Sarah
Casi, Giulio
Neri, Dario
MOLECULAR CANCER THERAPEUTICS, 2015, 14 (11) : 2606 - 2612
[34] Drug-Linkers in Antibody-Drug Conjugates: Perspective on Current Industry Practices
Bulger, Paul G.
Conlon, David A.
Cink, Russell D.
Fernandez-Cerezo, Lara
Zhang, Qunying
Thirumalairajan, Srinath
Raglione, Thomas
Liang, Ruiting
Zhou, Jinsheng
Chalgeri, Arun
ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2023, 27 (07) : 1248 - 1257
[35] Considerations for Starting Material Designation for Drug-Linkers in Antibody-Drug Conjugates
Jones, Michael T. T.
Dirat, Olivier
Conlon, David A. A.
Melucci, Charles
Schrier, Kate
Raglione, Thomas
Zhang, Qunying
Bulger, Paul G. G.
ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2023, 27 (07) : 1269 - 1275
[36] Synthesis of targeted small molecule drug conjugates employing a self-immolative disulfide/quaternary ammonium-based linker system
You, Fei
Kleindl, Paul
Reddy, Joseph
Vetzel, Marilynn
Nelson, Melissa
Leamon, Christopher
Vlahov, Iontcho
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2019, 258
[37] What's new in the use of antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) DNA cross-linkers for cancer therapy?
Hartley, John A.
EXPERT OPINION ON BIOLOGICAL THERAPY, 2023, 23 (11) : 1049 - 1052
[38] Discovery of novel linkers, payloads, and antibody-drug conjugates for the treatment of cancer
O'Donnell, Christopher
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2015, 250
[39] Antibody-Drug Conjugates Bearing Pyrrolobenzodiazepine or Tubulysin Payloads Are Immunomodulatory and Synergize with Multiple Immunotherapies
Rios-Doria, Jonathan
Harper, Jay
Rothstein, Raymond
Wetzel, Leslie
Chesebrough, Jon
Marrero, Allison
Chen, Cui
Strout, Patrick
Mulgrew, Kathy
McGlinchey, Kelly
Fleming, Ryan
Bezabeh, Binyam
Meekin, John
Stewart, David
Kennedy, Maureen
Martin, Philip
Buchanan, Andrew
Dimasi, Nazzareno
Michelotti, Emil
Hollingsworth, Robert
CANCER RESEARCH, 2017, 77 (10) : 2686 - 2698
[40] Anti-CD70 antibody-drug conjugates containing pyrrolobenzodiazepine dimers demonstrate robust antitumor activity
Jeffrey, Scott
Burke, Patrick
Meyer, David
Lyon, Robert
Miyamoto, Jamie
Anderson, Martha
Stone, Ivan
Law, Che-Leung
Senter, Peter
CANCER RESEARCH, 2012, 72

← 1 2 3 4 5 →