Research Papers:

Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design

Fumou Sun, Tong Wang, Jiahao Jiang, Yang Wang, Zhaoxiong Ma, Zhaoting Li, Yue Han, Mingzhu Pan, Jialing Cai, Min Wang and Juan Zhang _

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Oncotarget. 2017; 8:51238-51252. https://doi.org/10.18632/oncotarget.17228

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Fumou Sun1, Tong Wang1, Jiahao Jiang1, Yang Wang1, Zhaoxiong Ma1, Zhaoting Li1, Yue Han1, Mingzhu Pan1, Jialing Cai1, Min Wang1 and Juan Zhang1

1Antibody Engineering Laboratory, State Key Laboratory of Natural Medicines, Department of Molecular Biology, School of Life Science & Technology, China Pharmaceutical University, Nanjing 210009, PR China

Correspondence to:

Juan Zhang, email: [email protected]

Min Wang, email: [email protected]

Keywords: cluster of differentiation 24 (CD24), humanization, molecular operating environment (MOE), complementarity determining region (CDR) grafting, canonical residues

Received: February 14, 2017     Accepted: March 23, 2017     Published: April 19, 2017


Cluster of differentiation 24 (CD24) is a specific surface marker involved in the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, all reported anti-CD24 antibodies are murine ones with inevitable immunogenicity. To address this, a method using both molecular structure and docking-based complementarity determining region (CDR) grafting was employed for humanization. After xenogeneic CDR grafting into a human antibody, three types of canonical residues (in the VL/VH interface core, in the loop foundation, and interaction with loop residues) that support loop conformation and residues involved in the antigen-binding interface were back-mutated. Four engineered antibodies were produced, among which hG7-BM3 has virtually identical 3-D structure and affinity parameters with the parental chimeric antibody cG7. In vitro, hG7-BM3 demonstrated superior immunogenicity and serum stability to cG7. Antibody-dependent cellular cytotoxicity (ADCC), tumor cell internalization and in vivo targeting assays indicate that hG7-BM3 has the potential for development as an antibody-drug conjugate (ADC). We therefore generated the hG7-BM3-VcMMAE conjugate, which was shown to induce tumor cell apoptosis and effectively suppress nude mice bearing HCC xenografts. In conclusion, our study provides new inspiration for antibody humanization and an ADC candidate for laboratory study and clinical applications.

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