From therapeutic antibodies to chimeric antigen receptors (CARs): making better CARs based on antigen-binding domain.
A variety of approaches are being pursued to improve the safety and antitumor potency of chimeric antigen receptor (CAR) T-cell therapy. However, most engineering efforts have thus far been focused on its intracellular signaling domain, while its extracellular antigen-binding domain has received less attention. Areas covered: Herein, the authors summarize the current knowledge of CAR T-cell therapy. Accordingly, they focus on its antigen-binding domain, discuss key considerations for selecting an optimal single-chain variable fragment (scFv) when designing a CAR, and suggest potential directions aimed at developing the next-generation CARs. Expert opinion: The extracellular region of CARs can play a decisive role in their safety and efficacy. Instead of directly translating an available therapeutic mAb to a scFv-based CAR construct, the authors suggest that various CAR-displayed scFvs with different affinity, specificity and binding epitopes against an individual target molecule should be generated and evaluated side-by-side. Incorporating new antibody formats that possess characteristics superior to those of scFvs may be one way to engineer safer and more effective CARs. The authors expect that further CAR engineering will enable us to target more antigens involved in hematological and solid malignancies with minimal side effects to serve unmet clinical needs.
a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences , Fudan University , Shanghai , China.
Yanling
Y
Wu
a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences , Fudan University , Shanghai , China.
Shibo
S
Jiang
a Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences , Fudan University , Shanghai , China.
Tianlei
T
Ying
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002986:Clinical Trials as Topic / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology; D057127:Single-Chain Antibodies / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use
D011948:Receptors, Antigen, T-Cell; D057127:Single-Chain Antibodies
CAR; immunogenicity; mAb; scFv