The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens.
AuthorsGuest, Ryan D
Hawkins, Robert E
Cheadle, Eleanor J
O'Neill, Alison C
Irlam, Joely J
Chester, Kerry A
Kemshead, John T
Shaw, David M
Stern, Peter L
Gilham, David E
AffiliationCancer Research UK, Department of Medical Oncology, University of Manchester and Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
MetadataShow full item record
AbstractHuman peripheral blood lymphocytes can be transduced to express antigen-dependent CD3zeta chimeric immune receptors (CIRs), which function independently of the T-cell receptor (TCR). Although the exact function of these domains is unclear, previous studies imply that an extracellular spacer region is required for optimal CIR activity. In this study, four scFvs (in the context of CIRs with or without extracellular spacer regions) were used to target the human tumor-associated antigens carcinoembryonic antigen (CEA), neural cell adhesion molecule (NCAM), the oncofetal antigen 5T4, and the B-cell antigen CD19. In all cases human T-cell populations expressing the CIRs were functionally active against their respective targets, but the anti-5T4 and anti-NCAM CIRs showed enhanced specific cytokine release and cytotoxicity only when possessing an extracellular spacer region. In contrast, the anti-CEA and anti-CD19 CIRs displayed optimal cytokine release activity only in the absence of an extracellular spacer. Interestingly, mapping of the scFv epitopes has revealed that the anti-CEA scFv binds close to the amino-terminal of CEA, which is easily accessible to the CIR. In contrast, CIRs enhanced by a spacer domain appear to bind to epitopes residing closer to the cell membrane, suggesting that a more flexible extracellular domain may be required to permit the efficient binding of such epitopes. These results show that a spacer is not necessary for optimal activity of CIRs but that the optimal design varies.
CitationThe role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens., 28 (3):203-11 J. Immunother.
JournalJournal of Immunotherapy
- Primary polyclonal human T lymphocytes targeted to carcino-embryonic antigens and neural cell adhesion molecule tumor antigens by CD3zeta-based chimeric immune receptors.
- Authors: Gilham DE, O'Neil A, Hughes C, Guest RD, Kirillova N, Lehane M, Hawkins RE
- Issue date: 2002 Mar-Apr
- A fully human chimeric immune receptor for retargeting T-cells to CEA-expressing tumor cells.
- Authors: Shibaguchi H, Luo NX, Kuroki M, Zhao J, Huang J, Hachimine K, Kinugasa T, Kuroki M
- Issue date: 2006 Nov-Dec
- Construction and molecular characterization of human chimeric T-cell antigen receptors specific for carcinoembryonic antigen.
- Authors: Shirasu N, Shibaguci H, Kuroki M, Yamada H, Kuroki M
- Issue date: 2010 Jul
- Tumor-specific T cell activation by recombinant immunoreceptors: CD3 zeta signaling and CD28 costimulation are simultaneously required for efficient IL-2 secretion and can be integrated into one combined CD28/CD3 zeta signaling receptor molecule.
- Authors: Hombach A, Wieczarkowiecz A, Marquardt T, Heuser C, Usai L, Pohl C, Seliger B, Abken H
- Issue date: 2001 Dec 1
- Redirected activity of human antitumor chimeric immune receptors is governed by antigen and receptor expression levels and affinity of interaction.
- Authors: Turatti F, Figini M, Balladore E, Alberti P, Casalini P, Marks JD, Canevari S, Mezzanzanica D
- Issue date: 2007 Oct