Hypoxia-activated ADCC-enhanced humanized anti-CD147 antibody for liver cancer imaging and targeted therapy with improved selectivity
© 2024 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd..
Therapeutic antibodies (Abs) improve the clinical outcome of cancer patients. However, on-target off-tumor toxicity limits Ab-based therapeutics. Cluster of differentiation 147 (CD147) is a tumor-associated membrane antigen overexpressed in cancer cells. Ab-based drugs targeting CD147 have achieved inadequate clinical benefits for liver cancer due to side effects. Here, by using glycoengineering and hypoxia-activation strategies, we developed a conditional Ab-dependent cellular cytotoxicity (ADCC)-enhanced humanized anti-CD147 Ab, HcHAb18-azo-PEG5000 (HAP18). Afucosylated ADCC-enhanced HcHAb18 Ab was produced by a fed-batch cell culture system. Azobenzene (Azo)-linked PEG5000 conjugation endowed HAP18 Ab with features of hypoxia-responsive delivery and selective targeting. HAP18 Ab potently inhibits the migration, invasion, and matrix metalloproteinase secretion, triggers the cytotoxicity and apoptosis of cancer cells, and induces ADCC, complement-dependent cytotoxicity, and Ab-dependent cellular phagocytosis under hypoxia. In xenograft mouse models, HAP18 Ab selectively targets hypoxic liver cancer tissues but not normal organs or tissues, and has potent tumor-inhibiting effects. HAP18 Ab caused negligible side effects and exhibited superior pharmacokinetics compared to those of parent HcHAb18 Ab. The hypoxia-activated ADCC-enhanced humanized HAP18 Ab safely confers therapeutic efficacy against liver cancer with improved selectivity. This study highlights that hypoxia activation is a promising strategy for improving the tumor targeting potential of anti-CD147 Ab drugs.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
MedComm - 5(2024), 3 vom: 01. März, Seite e512 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Qi, Fang-Zheng [VerfasserIn] |
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| Links: |
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| Themen: |
Cluster of differentiation 147 |
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| Anmerkungen: |
Date Revised 13.03.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1002/mco2.512 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369592794 |
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| 520 | |a Therapeutic antibodies (Abs) improve the clinical outcome of cancer patients. However, on-target off-tumor toxicity limits Ab-based therapeutics. Cluster of differentiation 147 (CD147) is a tumor-associated membrane antigen overexpressed in cancer cells. Ab-based drugs targeting CD147 have achieved inadequate clinical benefits for liver cancer due to side effects. Here, by using glycoengineering and hypoxia-activation strategies, we developed a conditional Ab-dependent cellular cytotoxicity (ADCC)-enhanced humanized anti-CD147 Ab, HcHAb18-azo-PEG5000 (HAP18). Afucosylated ADCC-enhanced HcHAb18 Ab was produced by a fed-batch cell culture system. Azobenzene (Azo)-linked PEG5000 conjugation endowed HAP18 Ab with features of hypoxia-responsive delivery and selective targeting. HAP18 Ab potently inhibits the migration, invasion, and matrix metalloproteinase secretion, triggers the cytotoxicity and apoptosis of cancer cells, and induces ADCC, complement-dependent cytotoxicity, and Ab-dependent cellular phagocytosis under hypoxia. In xenograft mouse models, HAP18 Ab selectively targets hypoxic liver cancer tissues but not normal organs or tissues, and has potent tumor-inhibiting effects. HAP18 Ab caused negligible side effects and exhibited superior pharmacokinetics compared to those of parent HcHAb18 Ab. The hypoxia-activated ADCC-enhanced humanized HAP18 Ab safely confers therapeutic efficacy against liver cancer with improved selectivity. This study highlights that hypoxia activation is a promising strategy for improving the tumor targeting potential of anti-CD147 Ab drugs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a cluster of differentiation 147 | |
| 650 | 4 | |a hypoxia activation | |
| 650 | 4 | |a liver cancer | |
| 650 | 4 | |a on‐target off‐tumor toxicity | |
| 650 | 4 | |a therapeutic antibody | |
| 700 | 1 | |a Su, Hui-Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Luo-Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Chen-Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Ya-Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Dong-Mei |e verfasserin |4 aut | |
| 700 | 1 | |a Tang, Hao |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Jian-Li |e verfasserin |4 aut | |
| 700 | 1 | |a Bian, Hui-Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Zhi-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Si-He |e verfasserin |4 aut | |
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