Design of a mucin-selective protease for targeted degradation of cancer-associated mucins.

Autor: Pedram K; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA., Shon DJ; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Tender GS; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Mantuano NR; Cancer Immunotherapy Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.; Division of Oncology, Department of Theragnostics, University Hospital, Basel, Switzerland., Northey JJ; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco (UCSF), San Francisco, CA, USA., Metcalf KJ; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco (UCSF), San Francisco, CA, USA., Wisnovsky SP; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada., Riley NM; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Forcina GC; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Malaker SA; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA.; Department of Chemistry, Yale University, New Haven, CT, USA., Kuo A; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA., George BM; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA.; Brigham and Women's Hospital, Boston, MA, USA., Miller CL; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA., Casey KM; Department of Comparative Medicine, Stanford University, Stanford, CA, USA., Vilches-Moure JG; Department of Comparative Medicine, Stanford University, Stanford, CA, USA., Ferracane MJ; Department of Chemistry, University of Redlands, Redlands, CA, USA., Weaver VM; Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco (UCSF), San Francisco, CA, USA.; Departments of Radiation Oncology and Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and Helen Diller Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA, USA., Läubli H; Cancer Immunotherapy Laboratory, Department of Biomedicine, University of Basel, Basel, Switzerland.; Division of Oncology, Department of Theragnostics, University Hospital, Basel, Switzerland., Bertozzi CR; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA, USA. bertozzi@stanford.edu.; Howard Hughes Medical Institute, Stanford, CA, USA. bertozzi@stanford.edu.
Jazyk: angličtina
Zdroj: Nature biotechnology [Nat Biotechnol] 2024 Apr; Vol. 42 (4), pp. 597-607. Date of Electronic Publication: 2023 Aug 03.
DOI: 10.1038/s41587-023-01840-6
Abstrakt: Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.
(© 2023. The Author(s).)
Databáze: MEDLINE
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