Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer. Issue 3 (3rd April 2019)

• Record Type: Journal Article
• Authors: White, Jason B.; Fleming, Ryan; Masterson, Luke; Ruddle, Ben T.; Zhong, Haihong; Fazenbaker, Christine; Strout, Patrick; Rosenthal, Kim; Reed, Molly; Muniz-Medina, Vanessa; Howard, Philip; Dixit, Rakesh; Wu, Herren; Hinrichs, Mary Jane; Gao, Changshou; Dimasi, Nazzareno
• Is Part Of: MAbs. Volume 11:Issue 3(2019)
• Page Start: 500
• Page End: 515
• Publication Date: 2019-04-03
• Subjects: Antibody drug conjugates -- engineered antibodies -- site-specific conjugation -- pyrrolobenzodiazepine dimers -- cytotoxic payloads -- drug to antibody ratio; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2019.1578611
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: Most strategies used to prepare homogeneous site-specific antibody-drug conjugates (ADCs) result in ADCs with a drug-to-antibody ratio (DAR) of two. Here, we report a disulfide re-bridging strategy to prepare homogeneous ADCs with DAR of one using a dual-maleimide pyrrolobenzodiazepine (PBD) dimer (SG3710) and an engineered antibody (Flexmab), which has only one intrachain disulfide bridge at the hinge. We demonstrate that SG3710 efficiently re-bridge a Flexmab targeting human epidermal growth factor receptor 2 (HER2), and the resulting ADC was highly resistant to payload loss in serum and exhibited potent anti-tumor activity in a HER2-positive gastric carcinoma xenograft model. Moreover, this ADC was tolerated in rats at twice the dose compared to a site-specific ADC with DAR of two prepared using a single-maleimide PBD dimer (SG3249). Flexmab technologies, in combination with SG3710, provide a platform for generating site-specific homogenous PBD-based ADCs with DAR of one, which have improved biophysical properties and tolerability compared to conventional site-specific PBD-based ADCs with DAR of two.