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Updated: Jun 27, 2026
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Design optimization of antibody-ligand motifs to enhance CAR-T redirection activity against solid tumors
Xuechun Wang1, Shuhong Li1, Qiaoru Guo1
1State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
Abstract:
Antigenic heterogeneity and the tumor microenvironment remain major obstacles to effective chimeric antigen receptor T (CAR-T) therapy, but natural ligands engaging multiple antigens within tumors and their milieu offer a promising solution. Here, we present a multitarget switchable CAR-T (sCAR-T) strategy that integrates a universal receptor on T cells with an antibody-ligand motif, combining an anti-Her2 single-chain variable fragment (scFv) (4D5) and spliced VEGF-A (VEGF121) to target Her2, VEGFR1, and VEGFR2. Optimization of the switch and CAR hinge preserved the ligand's native dimeric conformation, enhancing antigen recognition and promoting immunological synapse formation. In syngeneic and xenograft models, sCAR-T achieves superior tumor eradication and vasculature disruption compared with conventional CAR-T, overcoming immune escape driven by antigenic heterogeneity. We further extend the sCAR-T design to target receptor tyrosine kinase-like orphan receptor 1 (ROR1), demonstrating that the antibody-ligand motif-based strategy provides a versatile framework for complex antigen targeting, with potential to improve efficacy and safety and enable broader application in immunotherapies targeting complex antigenic combinations.
Insights
A novel switchable chimeric antigen receptor T (sCAR-T) therapy targets multiple tumor antigens, overcoming immune escape and improving cancer treatment efficacy. This innovative approach enhances tumor eradication and vasculature disruption in preclinical models.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Antigenic heterogeneity and the tumor microenvironment hinder chimeric antigen receptor T (CAR-T) therapy efficacy.
- Natural ligands offer a potential solution by engaging multiple tumor antigens.
Purpose of the Study:
- To develop and evaluate a multitarget switchable CAR-T (sCAR-T) strategy.
- To overcome immune escape mechanisms in cancer therapy.
- To create a versatile platform for complex antigen targeting in immunotherapy.
Main Methods:
- Designed an sCAR-T strategy integrating a universal receptor with an antibody-ligand motif (anti-Her2 scFv and VEGF121).
- Optimized CAR hinge and switch for enhanced antigen recognition and immunological synapse formation.
- Tested sCAR-T efficacy in syngeneic and xenograft cancer models.
Main Results:
- sCAR-T demonstrated superior tumor eradication and vasculature disruption compared to conventional CAR-T.
- The strategy effectively overcame immune escape driven by antigenic heterogeneity.
- Extended sCAR-T design to target ROR1, showcasing versatility.
Conclusions:
- The antibody-ligand motif-based sCAR-T strategy provides a versatile framework for targeting complex antigen combinations.
- This approach holds potential for improved efficacy and safety in cancer immunotherapy.
- The sCAR-T platform may enable broader applications in treating diverse cancers.
