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

[41] Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody-Drug Conjugates
Shi, Wei
Zhang, Jianxin
Liu, Liya
Li, Wanzhen
Liu, Zhi
Ren, Anni
Wang, Jie
Tang, Caihong
Yang, Yang
Xu, Dandan
Huang, Qianqian
Wang, Yongqin
Luo, Caili
Huang, Wei
Tang, Feng
JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (01) : 1011 - 1026
[42] Bioanalytical methods for therapeutic monoclonal antibodies and antibody-drug conjugates: A review of recent advances and future perspectives
Todoroki, Kenichiro
Mizuno, Hajime
Sugiyama, Eiji
Toyo'oka, Toshimasa
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2020, 179
[43] Potent antitumor activity of anti-HER2 antibody-topoisomerase I inhibitor conjugate based on self-immolative dendritic dimeric-linker
Liubomirski, Yulia
Tiram, Galia
Scomparin, Anna
Gnaim, Samer
Das, Sayantan
Gholap, Sachin
Ge, Liang
Yeini, Eilam
Shelef, Omri
Zauberman, Arie
Berger, Nir
Kalimi, Doron
Toister-Achituv, Mira
Schroeter, Christian
Dickgiesser, Stephan
Tonillo, Jason
Shan, Min
Deutsch, Carl
Sweeney-Lasch, Stanley
Shabat, Doron
Satchi-Fainaro, Ronit
JOURNAL OF CONTROLLED RELEASE, 2024, 367 : 148 - 157
[44] Impact of cathepsin B-sensitive triggers and hydrophilic linkers on in vitro efficacy of novel site-specific antibody-drug conjugates
Bryden, Francesca
Martin, Camille
Letast, Stephanie
Lles, Eva
Vieitez-Villemin, Inmaculada
Rousseau, Anais
Colas, Cyril
Brachet-Botineau, Marie
Allard-Vannier, Emilie
Larbouret, Christel
Viaud-Massuard, Marie-Claude
Joubert, Nicolas
ORGANIC & BIOMOLECULAR CHEMISTRY, 2018, 16 (11) : 1882 - 1889
[45] Therapeutic effect of a MUC1-specific monoclonal antibody-drug conjugates against pancreatic cancer model
Wu, Guang
Li, Lan
Liu, Mengnan
Chen, Chunyan
Wang, Guangze
Jiang, Zewei
Qin, Yaqian
He, Licai
Li, Hongzhi
Cao, Jiawei
Gu, Haihua
CANCER CELL INTERNATIONAL, 2022, 22 (01)
[46] BCL-XL-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors
Judd, Andrew S.
Bawa, Bhupinder
Buck, Wayne R.
Tao, Zhi-Fu
Li, Yingchun
Mitten, Michael J.
Bruncko, Milan
Catron, Nathaniel
Doherty, George
Durbin, Kenneth R.
Enright, Brian
Frey, Robin
Haasch, Deanna
Haman, Sandra
Haight, Anthony R.
Henriques, Tracy A.
Holms, James
Izeradjene, Kamel
Judge, Russell A.
Jenkins, Gary J.
Kunzer, Aaron
Leverson, Joel D.
Martin, Ruth L.
Mitra, Diya
Mittelstadt, Scott
Nelson, Lorne
Nimmer, Paul
Palma, Joann
Peterson, Richard
Phillips, Darren C.
Ralston, Sherry L.
Rosenberg, Saul H.
Shen, Xiaoqiang
Song, Xiaohong
Vaidya, Kedar R.
Wang, Xilu
Wang, Jin
Xiao, Yu
Zhang, Haichao
Zhang, Xinxin
Blomme, Eric A.
Boghaert, Erwin R.
Kalvass, John C.
Phillips, Andrew
Souers, Andrew J.
SCIENCE ADVANCES, 2024, 10 (40):
[47] Reducing the antigen-independent toxicity of antibody-drug conjugates by minimizing their non-specific clearance through PEGylation
Simmons, Jessica K.
Burke, Patrick J.
Cochran, Julia H.
Pittman, Paul G.
Lyon, Robert P.
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2020, 392
[48] Immolation of p-Aminobenzyl Ether Linker and Payload Potency and Stability Determine the Cell-Killing Activity of Antibody-Drug Conjugates with Phenol-Containing Payloads
Zhang, Donglu
Le, Hoa
dela Cruz-Chuh, Josefa
Bobba, Sudheer
Guo, Jun
Staben, Leanna
Zhang, Chenghong
Ma, Yong
Kozak, Katherine R.
Phillips, Gail D. Lewis
Vollmar, Breanna S.
Sadowsky, Jack D.
Vandlen, Richard
Wei, BinQing
Su, Dian
Fan, Peter
Dragovich, Peter S.
Khojasteh, S. Cyrus
Hop, Cornelis E. C. A.
Pillow, Thomas H.
BIOCONJUGATE CHEMISTRY, 2018, 29 (02) : 267 - 274
[49] N-terminal selective conjugation method widens the therapeutic window of antibody-drug conjugates by improving tolerability and stability
Ko, Min Ji
Song, Daehae
Kim, Juhee
Kim, Jae Yong
Eom, Jaehyun
Sung, Byungje
Son, Yong-Gyu
Kim, Young Min
Lee, Sang Hoon
You, Weon-Kyoo
Jung, Jinwon
MABS, 2021, 13 (01)
[50] Site-Specific Conjugation of the Indolinobenzodiazepine DGN549 to Antibodies Affords Antibody-Drug Conjugates with an Improved Therapeutic Index as Compared with Lysine Conjugation
Bai, Chen
Reid, Emily E.
Wilhelm, Alan
Shizuka, Manami
Maloney, Erin K.
Laleau, Rassol
Harvey, Lauren
Archer, Katie E.
Vitharana, Dilrukshi
Adams, Sharlene
Kovtun, Yelena
Miller, Michael L.
Chari, Ravi
Keating, Thomas A.
Yoder, Nicholas C.
BIOCONJUGATE CHEMISTRY, 2020, 31 (01) : 93 - 103

← 1 2 3 4 5 →