Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

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) s...

Full description

Saved in:

Bibliographic Details
Published in:	Oncotarget Vol. 11; no. 1; pp. 31 - 45
Main Authors:	Okita, Kouki, Okazaki, Shogo, Uejima, Shinya, Yamada, Erina, Kaminaka, Hiroki, Kondo, Misa, Ueda, Shiho, Tokiwa, Ryo, Iwata, Nami, Yamasaki, Akitaka, Hayashi, Natsumi, Ogura, Dai, Hirotani, Kenji, Yoshioka, Toshiaki, Inoue, Masahiro, Masuko, Kazue, Masuko, Takashi
Format:	Journal Article
Language:	English
Published:	United States Impact Journals LLC 07-01-2020
Subjects:	Research Paper CDR internalization NRG1 HER3 mAb
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 tumor tissues and cancer tissue-originated spheroid. Ab4 inhibited 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1949-2553 1949-2553
DOI:	10.18632/oncotarget.27414