Switchable CAR-T Cells Outperformed Traditional Antibody-Redirected Therapeutics Targeting Breast Cancers.

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.

• Authors: Yu J Cao, Xuechun Wang, Zhidong Wang, Lijun Zhao, Shuhong Li, Zhuxia Zhang, Xiaoyi Wei, Hwayoung Yun, Sei-Hyun Choi, Zhong Liu, Lili Zhao, Stephanie A Kazane
• Journal: ACS synthetic biology (ACS Synth Biol) Vol. 10 Issue 5 Pg. 1176-1183 (05 21 2021) ISSN: 2161-5063 [Electronic] United States
• PMID: 33856201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Antibodies, Bispecific
• Antigens, Neoplasm
• IGF1R protein, human
• Immunoconjugates
• Receptors, Chimeric Antigen
• ERBB2 protein, human
• Receptor, ErbB-2
• Receptor, IGF Type 1
• Fluorescein-5-isothiocyanate

Topics

• Amino Acids (genetics)
• Antibodies, Bispecific (immunology)
• Antigenic Drift and Shift (immunology)
• Antigens, Neoplasm (immunology)
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Female
• Fluorescein-5-isothiocyanate
• Humans
• Immunoconjugates (immunology)
• Immunotherapy, Adoptive (methods)
• Molecular Targeted Therapy (methods)
• Receptor, ErbB-2 (immunology, metabolism)
• Receptor, IGF Type 1 (immunology, metabolism)
• Receptors, Chimeric Antigen (immunology)
• T-Lymphocytes (immunology)