One size does not fit all: navigating the multi-dimensional space to optimize T-cell engaging protein therapeutics

• Published in: mAbs Vol. 13; no. 1
• Main 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
• Format: Report
• Language: English
• Published: Taylor & Francis 01.01.2021
• Subjects: Bispecific engineering; cd3; t-cell engager; therapeutic window
• ISSN: 1942-0862; 1942-0870
• DOI: 10.1080/19420862.2020.1871171

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.