Fully human antibody VH domains to generate mono and bispecific CAR to target solid tumors
| Autor: | Hongxia Li, Giovanni Fucà, Brian Mcguinness, Hongwei Du, Elena Dukhovlinova, Xin Zhou, Colette Johnston, Peishun Shou, Guanmeng Wang, Gianpietro Dotti |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cytotoxicity
Immunologic Glutamate Carboxypeptidase II Male Cancer Research medicine.medical_treatment T-Lymphocytes MSLN Immunoglobulin Variable Region Lymphocyte Activation Immunotherapy Adoptive Mice Inbred NOD Immunology and Allergy RC254-282 Receptors Chimeric Antigen biology Chemistry Neoplasms. Tumors. Oncology. Including cancer and carcinogens CAR-T medicine.anatomical_structure Phenotype Oncology Mesothelin Antigens Surface Molecular Medicine Cytokines immunotherapy Antibody T cell Immunology Antigen Cell Line Tumor medicine PSMA Animals Humans Pharmacology Immune Cell Therapies and Immune Cell Engineering Humabody Prostatic Neoplasms tumor escape Immunotherapy Xenograft Model Antitumor Assays Chimeric antigen receptor In vitro Coculture Techniques Tumor Escape Cancer research biology.protein Single-Chain Antibodies |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 9, Iss 4 (2021) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundChimeric antigen receptor (CAR) T cells are effective in B-cell malignancies. However, heterogeneous antigen expression and antigen loss remain important limitations of targeted immunotherapy in solid tumors. Therefore, targeting multiple tumor-associated antigens simultaneously is expected to improve the outcome of CAR-T cell therapies. Due to the instability of single-chain variable fragments, it remains challenging to develop the simultaneous targeting of multiple antigens using traditional single-chain fragment variable (scFv)-based CARs.MethodsWe used Humabody VH domains derived from a transgenic mouse to obtain fully human prostate-specific membrane antigen (PSMA) VH and mesothelin (MSLN) VH sequences and redirect T cell with VH based-CAR. The antitumor activity and mode of action of PSMA VH and MSLN VH were evaluated in vitro and in vivo compared with the traditional scFv-based CARs.ResultsHuman VH domain-based CAR targeting PSMA and MSLN are stable and functional both in vitro and in vivo. VH modules in the bispecific format are capable of binding their specific target with similar affinity as their monovalent counterparts. Bispecific CARs generated by joining two human antibody VH domains can prevent tumor escape in tumor with heterogeneous antigen expression.ConclusionsFully human antibody VH domains can be used to generate functional CAR molecules, and redirected T cells elicit antitumoral responses in solid tumors at least as well as conventional scFv-based CARs. In addition, VH domains can be used to generate bispecific CAR-T cells to simultaneously target two different antigens expressed by tumor cells, and therefore, achieve better tumor control in solid tumors. |
| Databáze: | OpenAIRE |
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