2Department of Medical Biotechnology (Address Faculty of Medical Sciences Tarbiat Modares University Phone +98-21-88013030 Fax +98-21-88013030 P.O.Box 14115-331, Tehran , Iran Emial allameha@modares.ac.ir - Iran)
3School of Allied Medical Sciences (Hemat Highway , Next Milad Hospital , Tehran Medical Sicence University, Paramedics College ,Tehran - Iran Tel: +982188622766 Fax :+98188622533 E-mail : paramed_sec@tums.ac.ir - Iran)
Abstract : Despite the preclinical success of adoptive therapy with T cells bearing chimeric nanoconstructed antigen receptors (CARs), certain limitations of this therapeutic approach such as the immunogenicity of the antigen binding domain, the emergence of tumor cell escape variants and the blocking capacity of soluble antigen still remain. Here, we address these issues using a novel CAR binding moiety based on the oligoclonal camelid single domain antibodies. A unique set of 13 single domain antibodies were selected from an immunized camel phage library based on their target specificity and binding affinity. A combination of these single domain antibodies was used to generate four tumor associated glycoprotein (TAG-72)-specific CARs harboring an identical antigen binding site, but with different signaling and spacer domains. Although all four CARs were functionally active against the TAG-72 expressing tumor cells, the combination of CD3ζ, OX40, CD28 as well as the CH3-CH2-hinge-hinge domains most efficiently triggered T cell activation. Importantly, CAR mediated functions were not blocked by the soluble TAG-72 antigen at a supraphysiological concentration. Our approach may have the potential to reverse multiple tumor immune evasion mechanisms, avoid CAR immunogenicity, and overcome problems in cancer gene therapy with engineered nanoconstructs.
https://hal-riip.archives-ouvertes.fr/pasteur-00826029
Contributor : Fereidoun Mahboudi <>
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Zahra Sharifzadeh, Fatemeh Rahbarizadeh, Mohammad A Shokrgozar, Davoud Ahmadvand, Fereidoun Mahboudi, et al.. Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents.. Cancer Letters, Elsevier, 2012, epub ahead of print. ⟨10.1016/j.canlet.2012.08.010⟩. ⟨pasteur-00826029⟩