1. Switchable CAR-T Cells Outperformed Traditional Antibody-Redirected Therapeutics Targeting Breast Cancers
- Author
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Shuhong Li, Wang Zhidong, Lili Zhao, Lijun Zhao, Yu Cao, Xiaoyi Wei, Hwayoung Yun, Stephanie A. Kazane, Xuechun Wang, Zhong Liu, Zhuxia Zhang, and Sei-hyun Choi
- Subjects
0106 biological sciences ,Bispecific antibody ,Immunoconjugates ,Receptor, ErbB-2 ,T-Lymphocytes ,Biomedical Engineering ,Breast Neoplasms ,01 natural sciences ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Immunotherapy, Adoptive ,Receptor, IGF Type 1 ,03 medical and health sciences ,Breast cancer ,Antigen ,Antigens, Neoplasm ,010608 biotechnology ,Cell Line, Tumor ,Antibodies, Bispecific ,medicine ,Humans ,Molecular Targeted Therapy ,Amino Acids ,skin and connective tissue diseases ,Antigenic Drift and Shift ,030304 developmental biology ,Insulin-like growth factor 1 receptor ,0303 health sciences ,Receptors, Chimeric Antigen ,biology ,business.industry ,Cancer ,General Medicine ,medicine.disease ,Cancer cell ,biology.protein ,Cancer research ,Female ,Antibody ,Car t cells ,business ,Fluorescein-5-isothiocyanate - Abstract
Various antibody-redirected immunotherapeutic approaches, including antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor-T (CAR-T) cells, have been devised to produce specific activity against various cancer types. Using genetically encoded unnatural amino acids, we generated a homogeneous Her2-targeted ADC, a T cell-redirected bsAb, and a FITC-modified antibody capable of redirecting anti-FITC CAR-T (switchable CAR-T; sCAR-T) cells to target different Her2-expressing breast cancers. sCAR-T cells showed activity against Her2-expressing tumor cells comparable to that of conventional anti-Her2 CAR-T cells and superior to that of ADC- and bsAb-based approaches. To prevent antigen escape, we designed bispecific sCAR-T cells targeting both the Her2 receptor and IGF1R, which showed an overall improved activity against cancer cells with low Her2 expression. This study increases our understanding of various explored cancer therapeutics and underscores the efficient application of sCAR-T cells as a promising therapeutic option for breast cancer patients with low or heterogeneous antigen expression.
- Published
- 2021