Biological activity validation of a computationally designed Rituximab/CD3 T cell engager targeting CD20+ cancers with multiple mechanisms of action. (22nd October 2021)

• Record Type: Journal Article
• Authors: Cai, Wenyan; Dong, Jianbo; Gallolu Kankanamalage, Sachith; Titong, Allison; Shi, Jiadong; Jia, Zhejun; Wang, Bo; Huang, Cai; Zhang, Jing; Lin, Jun; Kan, Steven Z; Han, Shuhua; Zhou, Joe; Liu, Yue
• Is Part Of: Antibody therapeutics. Volume 4:Number 4(2021)
• Page Start: 228
• Page End: 241
• Publication Date: 2021-10-22
• Subjects: CD20/CD3 -- therapeutic antibodies -- bispecific antibodies -- T cell engager antibodies -- computer-aided antibody design; Immunoglobulins -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Therapeutic use -- Periodicals; Immunotechnology -- Periodicals; 616.0798
• DOI: 10.1093/abt/tbab024
• Languages: English
• ISSNs: 2516-4236

Abstract

Abstract: Background: Bispecific T cell engaging antibodies (TEAs) with one arm targeting a cancer antigen and another arm binding to CD3 have demonstrated impressive efficacy in multiple clinical studies. However, establishing a safety/efficacy balance remains challenging. For instance, some TEAs have severe safety issues. Additionally, not all patients or all cancer cells of one patient respond equally to TEAs. Methods: Here, we developed a next-generation bispecific TEA with better safety/efficacy balance and expanded mechanisms of action. Using the computer-aided antibody design strategy, we replaced heavy chain complementarity-determining regions (HCDRs) in one Rituximab arm with HCDRs from a CD3 antibody and generated a novel CD20/CD3 bispecific antibody. Results: After series of computer-aided sequence optimization, the lead molecule, GB261, showed great safety/efficacy balance both in vitro and in animal studies. GB261 exhibited high affinity to CD20 and ultra-low affinity to CD3. It showed comparable T cell activation and reduced cytokine secretion compared with a benchmark antibody (BM). ADCC and CDC caused by GB261 only killed CD20+ cells but not CD3+ cells. It exhibited better RRCL cell killing than the BM in a PBMC-engrafted, therapeutic treatment mouse model and good safety in cynomolgus monkeys. Conclusions: Thus, GB261 is a promising novel TEA against CD20+ cancers.