Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers
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Kouki Okita1,2,*, Shogo Okazaki1,3,*, Shinya Uejima1, Erina Yamada1, Hiroki Kaminaka1, Misa Kondo1, Shiho Ueda1, Ryo Tokiwa1, Nami Iwata1, Akitaka Yamasaki1, Natsumi Hayashi1, Dai Ogura4, Kenji Hirotani5, Toshiaki Yoshioka6, Masahiro Inoue7, Kazue Masuko1 and Takashi Masuko1
1 Cell Biology Laboratory, School of Pharmacy, Kindai University, Higashiosaka, Osaka, Japan
2 Production and Manufacturing, Carna Biosciences, Inc., BMA, Chuo-ku, Kobe, Japan
3 Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
4 Link Genomics, Inc., Chuo-ku, Tokyo, Japan
5 Oncology Clinical Development Department, R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan
6 Field of Basic Science, Department of Occupational therapy, Graduate School of Health Sciences, Akita University, Akita, Japan
7 Department of Clinical Bio-Resource Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
* These authors contributed equally to this work
|Takashi Masuko,||email:||[email protected]|
Keywords: CDR; HER3; internalization; mAb; NRG1
Received: August 28, 2019 Accepted: December 16, 2019 Published: January 07, 2020
Resistance of progressive cancers against chemotherapy is a serious clinical problem. In this context, human epidermal growth factor receptor 3 (HER3) can play important roles in drug resistance to HER1- and HER2- targeted therapies. Since clinical testing of anti-HER3 monoclonal antibodies (mAbs) such as patritumab could not show remarkable effect compared with existing drugs, we generated novel mAbs against anti-HER3. Novel rat mAbs reacted with HEK293 cells expressing HER3, but not with cells expressing HER1, HER2 or HER4. Specificity of mAbs was substantiated by the loss of mAb binding with knockdown by siRNA and knockout of CRISPR/Cas9-based genome-editing. Analyses of CDR sequence and germline segment have revealed that seven mAbs are classified to four groups, and the binding of patritumab was inhibited by one of seven mAbs. Seven mAbs have shown reactivity with various human epithelial cancer cells, strong internalization activity of cell-surface HER3, and inhibition of NRG1 binding, NRG1-dependent HER3 phosphorylation and cell growth. Anti-HER3 mAbs were also reactive with in vivo tumor tissues and cancer tissue-originated spheroid. Ab4 inhibited in vivo tumor growth of human colon cancer cells in nude mice. Present mAbs may be superior to existing anti-HER3 mAbs and support existing anti-cancer therapeutic mAbs.
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