한빛사논문
- 조회220
Injin Bang 1, Takamitsu Hattori 1,2, Nadia Leloup 1, Alexis Corrado 1, Atekana Nyamaa 1, Akiko Koide 1,3, Ken Geles 4, Elizabeth Buck 4 & Shohei Koide 1,2,*
1Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA.
2Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
3Division of Hematology Oncology, Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA.
4Black Diamond Therapeutics, New York, NY, USA.
*Corresponding author: correspondence to Shohei Koide
Abstract
Oncogenic mutations in the extracellular domain (ECD) of cell-surface receptors could serve as tumor-specific antigens that are accessible to antibody therapeutics. Such mutations have been identified in receptor tyrosine kinases including HER2. However, it is challenging to selectively target a point mutant, while sparing the wild-type protein. Here we developed antibodies selective to HER2 S310F and S310Y, the two most common oncogenic mutations in the HER2 ECD, via combinatorial library screening and structure-guided design. Cryogenic-electron microscopy structures of the HER2 S310F homodimer and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimics the dimerization arm of HER2 and thus inhibit HER2 dimerization. These antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro, and in vivo as a xenograft. These results validate HER2 ECD mutations as actionable therapeutic targets and offer promising candidates toward clinical development.
논문정보
- Research article
- 2024년 10월 (BRIC 등록일 2024-11-14)
- 국외 연구진
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