AAV delivered lysosome-targeting chimeras mediate sustained antibody depletion in vivo
- 1Stanford University
Abstract
Immunoglobulin G (IgG) is a critical effector of the adaptive immune system, but IgG autoantibodies against self-antigens drive pathology across a wide range of autoimmune diseases. Lowering circulating IgG is a validated and promising therapeutic avenue. Here we developed genetically-encoded lysosome targeting chimeras (GELYTACs) that target circulating IgGs for clearance and degradation. The GELYTACs comprised two protein modules derived from insulin-like growth factor 2 (IGF2) and an IgG-binding nanobody, respectively, and mediated clearance of plasma IgG via the lysosomal trafficking receptor IGF2R. To achieve long-lasting IgG depletion, we encoded GELYTACs in an AAV gene therapy vector and established continuous expression in mice. We also developed conditional GELYACs that are activatable with disease-specific proteases or small molecule drugs and show that GELYTACs can be secreted from cellular therapies. This work establishes GELYTACs as a possible therapeutic modality that is deliverable using genetic medicine approaches.
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BibTeX
@misc{yang2026delivered,
title = {{AAV delivered lysosome-targeting chimeras mediate sustained antibody depletion in vivo}},
author = {J. L. Yang and K. Y. Loh and C. R. Sandoval Espinoza and D. Schuster and S. A. Yamada-Hunter and L. Labanieh and E. Sotillo and C. Mackall and K. Deisseroth and C. Bertozzi},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.05.736665},
url = {https://www.biorxiv.org/content/10.64898/2026.07.05.736665v3},
note = {CC BY},
}
RIS
TY - UNPB
TI - AAV delivered lysosome-targeting chimeras mediate sustained antibody depletion in vivo
AU - J. L. Yang
AU - K. Y. Loh
AU - C. R. Sandoval Espinoza
AU - D. Schuster
AU - S. A. Yamada-Hunter
AU - L. Labanieh
AU - E. Sotillo
AU - C. Mackall
AU - K. Deisseroth
AU - C. Bertozzi
PY - 2026
DA - 2026/07/05
PB - bioRxiv
DO - 10.64898/2026.07.05.736665
UR - https://www.biorxiv.org/content/10.64898/2026.07.05.736665v3
AB - Immunoglobulin G (IgG) is a critical effector of the adaptive immune system, but IgG autoantibodies against self-antigens drive pathology across a wide range of autoimmune diseases. Lowering circulating IgG is a validated and promising therapeutic avenue. Here we developed genetically-encoded lysosome targeting chimeras (GELYTACs) that target circulating IgGs for clearance and degradation. The GELYTACs comprised two protein modules derived from insulin-like growth factor 2 (IGF2) and an IgG-binding nanobody, respectively, and mediated clearance of plasma IgG via the lysosomal trafficking receptor IGF2R. To achieve long-lasting IgG depletion, we encoded GELYTACs in an AAV gene therapy vector and established continuous expression in mice. We also developed conditional GELYACs that are activatable with disease-specific proteases or small molecule drugs and show that GELYTACs can be secreted from cellular therapies. This work establishes GELYTACs as a possible therapeutic modality that is deliverable using genetic medicine approaches.
ER -