One size does not fit all: navigating the multi-dimensional space to optimize T-cell engaging protein therapeutics. Issue 1 (1st January 2021)

• Record Type: Journal Article
• Authors: Chen, Wei; Yang, Fan; Wang, Carole; Narula, Jatin; Pascua, Edward; Ni, Irene; Ding, Sheng; Deng, Xiaodi; Chu, Matthew Ling-Hon; Pham, Amber; Jiang, Xiaoyue; Lindquist, Kevin C.; Doonan, Patrick J.; Van Blarcom, Tom; Yeung, Yik Andy; Chaparro-Riggers, Javier
• Is Part Of: MAbs. Volume 13:Issue 1(2021)
• Publication Date: 2021-01-01
• Subjects: Bispecific engineering -- cd3 -- t-cell engager -- therapeutic window; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2020.1871171
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: T-cell engaging biologics is a class of novel and promising immune-oncology compounds that leverage the immune system to eradicate cancer. Here, we compared and contrasted a bispecific diabody-Fc format, which displays a relatively short antigen-binding arm distance, with our bispecific IgG platform. By generating diverse panels of antigen-expressing cells where B cell maturation antigen is either tethered to the cell membrane or located to the juxtamembrane region and masked by elongated structural spacer units, we presented a systematic approach to investigate the role of antigen epitope location and molecular formats in immunological synapse formation and cytotoxicity. We demonstrated that diabody-Fc is more potent for antigen epitopes located in the membrane distal region, while bispecific IgG is more efficient for membrane-proximal epitopes. Additionally, we explored other parameters, including receptor density, antigen-binding affinity, and kinetics. Our results show that molecular format and antigen epitope location, which jointly determine the intermembrane distance between target cells and T cells, allow decoupling of cytotoxicity and cytokine release, while antigen-binding affinities appear to be positively correlated with both readouts. Our work offers new insight that could potentially lead to a wider therapeutic window for T-cell engaging biologics in general.