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Updated: Jul 12, 2026
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Hypoxia-activated ADCC-enhanced humanized anti-CD147 antibody for liver cancer imaging and targeted therapy with
Fang-Zheng Qi1, Hui-Shan Su1, Bo Wang1
1Department of Cell Biology, School of Medicine Nankai University Tianjin China.
Abstract:
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.
Insights
A novel hypoxia-activated antibody (HAP18) targets liver cancer by enhancing antibody-dependent cellular cytotoxicity (ADCC) specifically in tumors. This approach improves therapeutic efficacy and reduces side effects compared to traditional antibody treatments.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Therapeutic antibodies (Abs) offer clinical benefits for cancer but face limitations due to on-target, off-tumor toxicity.
- Cluster of differentiation 147 (CD147) is a tumor antigen overexpressed in liver cancer, but CD147-targeting Abs have shown limited efficacy and side effects.
Purpose of the Study:
- To develop a hypoxia-activated, antibody-dependent cellular cytotoxicity (ADCC)-enhanced humanized anti-CD147 antibody (HAP18) for improved liver cancer therapy.
- To enhance the selectivity and efficacy of anti-CD147 antibody treatment by leveraging hypoxia-responsive delivery.
Main Methods:
- Glycoengineering and hypoxia-activation strategies were employed to create HAP18, an afucosylated ADCC-enhanced humanized anti-CD147 antibody.
- Azobenzene (Azo)-linked PEG5000 conjugation was used for hypoxia-responsive delivery and selective targeting.
- In vitro and in vivo studies using xenograft mouse models were conducted to evaluate HAP18's efficacy and safety.
Main Results:
- HAP18 demonstrated potent inhibition of cancer cell migration, invasion, and matrix metalloproteinase secretion.
- The antibody induced ADCC, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis specifically under hypoxia.
- HAP18 selectively targeted hypoxic liver cancer tissues in vivo, exhibiting significant tumor inhibition with negligible side effects and improved pharmacokinetics.
Conclusions:
- Hypoxia activation is a promising strategy for enhancing the tumor-targeting potential of anti-CD147 antibody drugs.
- The developed HAP18 antibody offers a safe and effective therapeutic approach for liver cancer with improved selectivity.
- This study validates the potential of conditional ADCC enhancement for targeted cancer immunotherapy.
