Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity

Alessia Gravina; Grigol Tediashvili; Yueting Zheng; Kumiko A Iwabuchi; Sara M Peyrot; Susan Z Roodsari; Lauren Gargiulo; Shin Kaneko; Mitsujiro Osawa; Sonja Schrepfer; Tobias Deuse

doi:10.1016/j.stem.2023.10.003

Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity

Cell Stem Cell. 2023 Nov 2;30(11):1538-1548.e4. doi: 10.1016/j.stem.2023.10.003.

Affiliations

¹ Transplant and Stem Cell Immunobiology (TSI)-Lab, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
² Shinobi Therapeutics, 2 Tower Place, South San Francisco, CA 94080, USA.
³ Laboratory of Regenerative Immunotherapy, Department of Cell Growth and Differentiation, Center for iPS cell Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
⁴ Shinobi Therapeutics, Med-Pharm Collaboration Building 46-29, Yoshida-Shimo-Adachi-Cho, Sakyo-Ku, Kyoto, Japan.
⁵ Transplant and Stem Cell Immunobiology (TSI)-Lab, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: tobias.deuse@ucsf.edu.

PMID: 37922880
DOI: 10.1016/j.stem.2023.10.003

Abstract

Immune rejection of allogeneic cell therapeutics remains a major problem for immuno-oncology and regenerative medicine. Allogeneic cell products so far have inferior persistence and efficacy when compared with autologous alternatives. Engineering of hypoimmune cells may greatly improve their therapeutic benefit. We present a new class of agonistic immune checkpoint engagers that protect human leukocyte antigen (HLA)-depleted induced pluripotent stem cell-derived endothelial cells (iECs) from innate immune cells. Engagers with agonistic functionality to their inhibitory receptors TIM3 and SIRPα effectively protect engineered iECs from natural killer (NK) cell and macrophage killing. The SIRPα engager can be combined with truncated CD64 to generate fully immune evasive iECs capable of escaping allogeneic cellular and immunoglobulin G (IgG) antibody-mediated rejection. Synthetic immune checkpoint engagers have high target specificity and lack retrograde signaling in the engineered cells. This modular design allows for the exploitation of more inhibitory immune pathways for immune evasion and could contribute to the advancement of allogeneic cell therapeutics.

Keywords: hypoimmune editing; immune checkpoints; immune evasion.

MeSH terms

Endothelial Cells / metabolism
HLA Antigens
Humans
Immunity, Innate
Induced Pluripotent Stem Cells* / metabolism
Killer Cells, Natural

Substances

HLA Antigens