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

Mol Ther. 2021 Dec 1;29(12):3398-3409. doi: 10.1016/j.ymthe.2021.06.022. Epub 2021 Jul 2.


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.

Keywords: CAR T cells; IdeS; anti-CAR IgG; cell therapies; humoral response; immunogenicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Immunoglobulin G*
  • Phagocytosis
  • Receptors, Chimeric Antigen* / metabolism


  • Immunoglobulin G
  • Receptors, Chimeric Antigen