Format

Send to

Choose Destination
Front Oncol. 2019 Aug 2;9:717. doi: 10.3389/fonc.2019.00717. eCollection 2019.

High-Affinity Human Anti-c-Met IgG Conjugated to Oxaliplatin as Targeted Chemotherapy for Hepatocellular Carcinoma.

Ma Y1, Zhang M1, Wang J1, Huang X2,3, Kuai X2,3, Zhu X1, Chen Y4, Jia L2,3, Feng Z2,3,5, Tang Q2, Liu Z1.

Author information

1
Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
2
Key Laboratory of Antibody Techniques of National Health Commission, Nanjing Medical University, Nanjing, China.
3
Department of Pathology, Nanjing Medical University, Nanjing, China.
4
Otorhinolaryngological Department, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
5
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.

Abstract

Hepatocellular carcinoma (HCC) is one of the most mortality-causing solid cancers globally and the second largest cause of death among malignancies. Oxaliplatin, a platinum-based drug, has been widely utilized in the treatment of malignancies such as colorectal cancer and hepatocellular carcinoma, yet its usage is limited because of severe side effects of cytotoxicity to normal tissues. c-Met, a receptor tyrosine kinase, is expressed aberrantly on the surface of HCC. The purpose of this study was to synthesise a humanized antibody against c-Met (anti-c-Met IgG) and conjugate it to oxaliplatin to develop a novel antibody-drug conjugate (ADC). Anti-c-Met IgG was detected to be loaded with ~4.35 moles oxaliplatin per mole of antibody. ELISA and FCM confirmed that ADC retained a high and selective binding affinity for c-Met protein and c-Met-positive HepG2 cells. In vitro, the cytotoxicity tests and biological function assay indicated that ADC showed much higher cytotoxicity and functioning in c-Met-positive HepG2 cells, compared with shMet-HepG2 cells expressing lower levels of c-Met. Furthermore, compared with free oxaliplatin, ADC significantly improved cytotoxicity to c-Met-positive tumours and avoided off-target cell toxicity in vivo. In conclusion, by targeting c-Met-expressing hepatoma cells, ADC can provide a platform to reduce drug toxicity and improve drug efficacy in vitro and in vivo.

KEYWORDS:

antibody-drug conjugate; c-Met; hepatocellular carcinoma; oxaliplatin; targeted chemotherapy

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center