Journal article
Targeted glycan degradation potentiates the anticancer immune response in vivo.
- Gray MA Department of Chemistry, Stanford University, Stanford, CA, USA.
- Stanczak MA Cancer Immunology Laboratory, Department of Biomedicine, University Hospital, Basel, Switzerland.
- Mantuano NR Cancer Immunology Laboratory, Department of Biomedicine, University Hospital, Basel, Switzerland.
- Xiao H Department of Chemistry, Stanford University, Stanford, CA, USA.
- Pijnenborg JFA Department of Chemistry, Stanford University, Stanford, CA, USA.
- Malaker SA Department of Chemistry, Stanford University, Stanford, CA, USA.
- Miller CL Department of Bioengineering, Stanford University, Stanford, CA, USA.
- Weidenbacher PA Department of Chemistry, Stanford University, Stanford, CA, USA.
- Tanzo JT Department of Chemistry, Stanford University, Stanford, CA, USA.
- Ahn G Department of Chemistry, Stanford University, Stanford, CA, USA.
- Woods EC Department of Chemistry, Stanford University, Stanford, CA, USA.
- Läubli H Cancer Immunology Laboratory, Department of Biomedicine, University Hospital, Basel, Switzerland.
- Bertozzi CR Department of Chemistry, Stanford University, Stanford, CA, USA. bertozzi@stanford.edu.
- 2020-08-19
Published in:
- Nature chemical biology. - 2020
English
Currently approved immune checkpoint inhibitor therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, most patients across cancer types still fail to respond. Consequently, there is interest in discovering and blocking alternative pathways that mediate immune suppression. One such mechanism is an upregulation of sialoglycans in malignancy, which has been recently shown to inhibit immune cell activation through multiple mechanisms and therefore represents a targetable glycoimmune checkpoint. Since these glycans are not canonically druggable, we designed an αHER2 antibody-sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells. In syngeneic breast cancer models, desialylation enhanced immune cell infiltration and activation and prolonged the survival of mice, an effect that was dependent on expression of the Siglec-E checkpoint receptor found on tumor-infiltrating myeloid cells. Thus, antibody-sialidase conjugates represent a promising modality for glycoimmune checkpoint therapy.
- Language
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- English
- Open access status
- closed
- Identifiers
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- DOI 10.1038/s41589-020-0622-x
- PMID 32807964
- Persistent URL
- https://sonar.ch/global/documents/93731
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