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Research Article
Yue Liu
Ab Studio Inc.
Corresponding Author
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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. 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. 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 to a benchmark antibody (BM). GB261-induced ADCC and CDC 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. Thus, GB261 is a promising novel TEA against CD20+ cancers.
Keywords
T cell engaging antibodies, safety, expanded mechanisms, heavy chain complementarity-determining regions, Rituximab arm
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Competing interest reported. Wenyan Cai is a former employee of Ab Studio Inc. and currently works at Genor Biopharma Co. Ltd. Jianbo Dong, Sachith Gallolu Kankanamalage, Allison Titong, and Bo Wang are employees of Ab Studio Inc. Jiadong Shi and Zhejun Jia are former employees at Ab Studio Inc. Cai Huang is an employee at Ab Therapeutics Inc. Jing Zhang, Jun Lin, Steven Z. Kan, and Joe Zhou are employees of Genor Biopharma Co. Ltd. Yue Liu is the Founder of Ab Studio Inc. and Ab Therapeutics Inc. Ab Studio Inc., Ab Therapeutics Inc., and Genor Biopharma Co. Ltd. are actively engaged in the commercial development of therapeutic antibodies.
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research Article
Yue Liu
Ab Studio Inc.
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
View the published article at Antibody Therapeutics.
Version 1
Posted 16 Mar, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Antibody Therapeutics.
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. 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. 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 to a benchmark antibody (BM). GB261-induced ADCC and CDC 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. Thus, GB261 is a promising novel TEA against CD20+ cancers.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Competing interest reported. Wenyan Cai is a former employee of Ab Studio Inc. and currently works at Genor Biopharma Co. Ltd. Jianbo Dong, Sachith Gallolu Kankanamalage, Allison Titong, and Bo Wang are employees of Ab Studio Inc. Jiadong Shi and Zhejun Jia are former employees at Ab Studio Inc. Cai Huang is an employee at Ab Therapeutics Inc. Jing Zhang, Jun Lin, Steven Z. Kan, and Joe Zhou are employees of Genor Biopharma Co. Ltd. Yue Liu is the Founder of Ab Studio Inc. and Ab Therapeutics Inc. Ab Studio Inc., Ab Therapeutics Inc., and Genor Biopharma Co. Ltd. are actively engaged in the commercial development of therapeutic antibodies.
This is a list of supplementary files associated with this preprint. Click to download.
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