Screening and Identification of a Novel Anti-siglec-15 Human Antibody 3F1 and the Research on Its Antitumor Activity

35 Pages Posted: 28 Oct 2021

See all articles by Jiaguo Wu

Jiaguo Wu

Dali University - Department of Anatomy

Jingyi Peng

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Yangyihua Zhou

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Ran Zhang

Hunan Normal University - School of Medicine

Zhihong Wang

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Naijing Hu

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Dingmu Zhang

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Guiqi Quan

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Yuanyu Wu

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Jiannan Feng

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Beifen Shen

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Jian Zhao

Henan University - Joint National Laboratory for Antibody Drug Engineering

Yan Zhang

Government of the People's Republic of China - Department of Obstetrics and Gynecology

Kaiming Yang

Dali University - Department of Anatomy

Longlong Luo

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures

Abstract

Siglec-15, as an important immunosuppressive molecule, is considered as an important target in the next generation of tumor immunotherapy. In this study, we screened multiple high affinity antibodies that specifically recognized human siglec-15 by using human phage antibody library with large capacity, and verified their binding, blocking and biological activities in vitro and in vivo. The results showed that the selected antibodies could effectively bind to siglec-15 overexpressed cell lines. As the reported ligands of siglec-15, the binding activity of siglec-15 and sialyl-Tn, CD44, MAG and LRRC4C can be blocked by 3 of the candidate antibodies, among them, 3F1 has a competitive advantage, which indicate 3F1 can effectively breaking down the tumor microenvironment by siglec-15 immunosuppressive signals. In addition, 3F1 antibody could reverse the inhibitory effect of siglec-15 on lymphocyte proliferation (especially CD4+T, CD8+T) and cytokine release (IFN-γ). In the tumor model of Balb/c Nude mice, mice were subcutaneously inoculated with genetically modified human non-small-cell lung carcinoma cell line H157 (overexpressed with siglec-15), compared with PBS group, 3F1 showed certain anti-tumor effect, moreover, the combination of 3F1 and ERBITUX showed significant antitumor effect (p<0.05). In conclusion, a novel human antibody 3F1 targeting human siglec-15 was obtained from phage display. The antibody has certain anti-tumor activity and is expected to be an innovative candidate drug targeting siglec-15 for tumor immunotherapy.

Funding: This research was supported by the National Natural Sciences Foundation of China grant (No. 31771010, No. 81700122).

Declaration of Interests: The authors declare no conflict of interest

Animal Care Committee Approval Statement: The Experimental Animal Management and use committee of my institute has reviewed the Animal Experiment Program and approved it.

Keywords: siglec-15, immune checkpoint molecules, tumor immunotherapy, human phage antibody library, ligands

Suggested Citation

Wu, Jiaguo and Peng, Jingyi and Zhou, Yangyihua and Zhang, Ran and Wang, Zhihong and Hu, Naijing and Zhang, Dingmu and Quan, Guiqi and Wu, Yuanyu and Feng, Jiannan and Shen, Beifen and Zhao, Jian and Zhang, Yan and Yang, Kaiming and Luo, Longlong, Screening and Identification of a Novel Anti-siglec-15 Human Antibody 3F1 and the Research on Its Antitumor Activity. Available at SSRN: https://ssrn.com/abstract=3946270 or http://dx.doi.org/10.2139/ssrn.3946270

Jiaguo Wu

Dali University - Department of Anatomy ( email )

Dali
China

Jingyi Peng

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Yangyihua Zhou

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Ran Zhang

Hunan Normal University - School of Medicine ( email )

No. 36, Lushan Road
Yuelu District
Changsha, Hunan 410001
China

Zhihong Wang

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Naijing Hu

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Dingmu Zhang

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Guiqi Quan

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Yuanyu Wu

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Jiannan Feng

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Beifen Shen

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

Jian Zhao

Henan University - Joint National Laboratory for Antibody Drug Engineering ( email )

Kaifeng
China

Yan Zhang

Government of the People's Republic of China - Department of Obstetrics and Gynecology ( email )

Beijing
China

Kaiming Yang

Dali University - Department of Anatomy ( email )

Dali
China

Longlong Luo (Contact Author)

Institute of Pharmacology and Toxicology - State Key Laboratory of Toxicology and Medical Countermeasures ( email )

Beijing
China

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