Biological activity validation of a computationally designed Rituximab/CD3 T cell engager targeting CD20+ cancers with multiple mechanisms of action
© The Author(s) 2021. Published by Oxford University Press on behalf of Antibody Therapeutics..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
Antibody therapeutics - 4(2021), 4 vom: 10. Okt., Seite 228-241 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cai, Wenyan [VerfasserIn] |
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| Links: |
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| Themen: |
Bispecific antibodies |
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| Anmerkungen: |
Date Revised 28.04.2022 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1093/abt/tbab024 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM333430808 |
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| 520 | |a © The Author(s) 2021. Published by Oxford University Press on behalf of Antibody Therapeutics. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: Thus, GB261 is a promising novel TEA against CD20+ cancers | ||
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| 700 | 1 | |a Zhang, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Kan, Steven Z |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Shuhua |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Joe |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yue |e verfasserin |4 aut | |
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