Incorporation of bacterial immunoevasins to protect cell therapies from host antibody-mediated immune rejection

Leila Peraro, Christopher M. Bourne, Megan M. Dacek, Enver Akalin, Jae H. Park, Eric L. Smith, David A. Scheinberg

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Cellular therapies are engineered using foreign and synthetic protein sequences, such as chimeric antigen receptors (CARs). The frequently observed humoral responses to CAR T cells result in rapid clearance, especially after re-infusions. There is an unmet need to protect engineered cells from host-versus-graft rejection, particularly for the advancement of allogeneic cell therapies. Here, utilizing the immunoglobulin G (IgG) protease “IdeS,” we programmed CAR T cells to defeat humoral immune attacks. IdeS cleavage of host IgG averted Fc-dependent phagocytosis and lysis, and the residual F(ab′)2 fragments remained on the surface, providing cells with an inert shield from additional IgG deposition. “Shield” CAR T cells efficiently cleaved cytotoxic IgG, including anti-CAR antibodies, detected in patient samples and provided effective anti-tumor activity in the presence of anti-cell IgG in vivo. This technology may be useful for repeated human infusions of engineered cells, more complex engineered cells, and expanding widespread use of “off-the-shelf” allogeneic cellular therapies.

Original languageEnglish (US)
Pages (from-to)3398-3409
Number of pages12
JournalMolecular Therapy
Volume29
Issue number12
DOIs
StatePublished - Dec 1 2021

Keywords

  • CAR T cells
  • IdeS
  • anti-CAR IgG
  • cell therapies
  • humoral response
  • immunogenicity

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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