Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents

Zahra Sharifzadeh, Fatemeh Rahbarizadeh, Mohammad A. Shokrgozar, Davoud Ahmadvand, Fereidoun Mahboudi, Fatemeh Rahimi Jamnani, S. Moein Moghimi

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)237-244
Number of pages8
JournalCancer Letters
Volume334
Issue number2
DOIs
StatePublished - Jul 1 2013

Keywords

  • Chimeric antigen receptor
  • Oligoclonal single domain antibodies
  • TAG-72

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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