Targeted suppression of autoimmune diseases without collateral suppression of normal immunity remains an elusive yet clinically important goal. Targeted blockade of programmed-cell-death-protein-1 (PD-1)—an immune checkpoint factor expressed by activated T cells and B cells—is an efficacious therapy for potentiating immune activation against tumours. Here we show that an immunotoxin consisting of an anti-PD-1 single-chain variable fragment, an albumin-binding domain and Pseudomonas exotoxin targeting PD-1-expressing cells, selectively recognizes and induces the killing of the cells. Administration of the immunotoxin to mouse models of autoimmune diabetes delays disease onset, and its administration in mice paralysed by experimental autoimmune encephalomyelitis ameliorates symptoms. In all mouse models, the immunotoxin reduced the numbers of PD-1-expressing cells, of total T cells and of cells of an autoreactive T-cell clone found in inflamed organs, while maintaining active adaptive immunity, as evidenced by full-strength immune responses to vaccinations. The targeted depletion of PD-1-expressing cells contingent to the preservation of adaptive immunity might be effective in the treatment of a wide range of autoimmune diseases.
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We thank X. Wang and H. Dai for their assistance in breeding mice. The flow cytometry work was conducted in the Flow Cytometry Core Facility of University of Utah. We thank Y. Zhang and J. Wang for their review and comments on the statistical analysis of this study and S. Owen and A. Dixon for their technical assistance with antibody-related protein engineering. S.J.F. was supported by grants NS070235 and JDRF 2-SRA-2014–270-M-R. R.S.F. was supported by grants R01NS065714, R01NS082102 and R01NS091939. S.G.Z. was supported by grants R01AR059103 and R61AR073409, and the NIH Star Award. P.Z. was supported by a Graduate Research Fellowship from the University of Utah. This work was primarily supported by the University of Utah Start-up Fund, a Huntsman Cancer Institute Pilot Grant (Grant number 170301), and party by a NIH grant (R21EB024083) to M.C.
M.C., P.Z. and P.W. have a pending patent application related to this work.
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Nature Biomedical Engineering (2019)