Conjugation of Indoles to Antibodies through a Novel Self‐Immolating Linker
Authors:
- Peter S. DragovichPDPeter S. Dragovich
- Robert A. BlakeRBRobert A. Blake
- Chunjiao ChenCCChunjiao Chen
- Jinhua ChenJCJinhua Chen
- Josefa ChuhJCJosefa Chuh
- Willem Den BestenWBWillem Den Besten
- Fang FanFFFang Fan
- Aimee FourieAFAimee Fourie
- Steven J. HartmanSHSteven J. Hartman
- Changrong HeCHChangrong He
- Jintang HeJHJintang He
- Ellen Rei IngallaEIEllen Rei Ingalla
- 25 March 2018
- journal article
- research article
- Published by Wiley in Chemistry – A European Journal
- Vol. 24 (19) , 4830-4834
Abstract
A novel strategy to attach indole‐containing payloads to antibodies through a carbamate moiety and a self‐immolating, disulfide‐based linker is described. This new strategy was employed to connect a selective estrogen receptor down‐regulator (SERD) to various antibodies in a site‐selective manner. The resulting conjugates displayed potent, antigen‐dependent down‐regulation of estrogen receptor levels in MCF7‐neo/HER2 and MCF7‐hB7H4 cells. They also exhibited similar antigen‐dependent modulation of the estrogen receptor in tumors when administered intravenously to mice bearing MCF7‐neo/HER2 tumor xenografts. The indole‐carbamate moiety present in the new linker was stable in whole blood from various species and also exhibited good in vivo stability properties in mice.Keywords
This publication has 24 references indexed in Scilit:
- Current ADC Linker ChemistryPharmaceutical Research, 2015
- The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast CancersMolecular Cancer Therapeutics, 2015
- An Immunosuppressive Antibody–Drug ConjugateJournal of the American Chemical Society, 2015
- Site-Specific Antibody–Drug Conjugates: The Nexus of Bioorthogonal Chemistry, Protein Engineering, and Drug DevelopmentBioconjugate Chemistry, 2014
- Ado-trastuzumab Emtansine (T-DM1): An Antibody–Drug Conjugate (ADC) for HER2-Positive Breast Cancer2014
- A Potent Anti-CD70 Antibody–Drug Conjugate Combining a Dimeric Pyrrolobenzodiazepine Drug with Site-Specific Conjugation TechnologyBioconjugate Chemistry, 2013
- Biomedical Importance of IndolesMolecules, 2013
- The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphomaNature Biotechnology, 2012
- Disulfide-Linked Antibody−Maytansinoid Conjugates: Optimization of In Vivo Activity by Varying the Steric Hindrance at Carbon Atoms Adjacent to the Disulfide LinkageBioconjugate Chemistry, 2011
- Development of potent monoclonal antibody auristatin conjugates for cancer therapyNature Biotechnology, 2003