Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 12, Pages 1376-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41589-020-0622-x
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Funding
- Goldschmidt-Jacobson Foundation
- Promedica Foundation
- Swiss National Science Foundation [310030_184720/1]
- National Institutes of Health [NIH CA227942]
- National Science Foundation Graduate Research Fellowship
- Stanford ChEM-H Chemistry/Biology Interface Predoctoral Training Program
- Swiss Government Excellence Scholarship for Foreign Scholars and Artists
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Stanford Undergraduate Summer Research Program in Chemistry through Stanford VPUE/UAR
- US National Institutes of Health [F31CA200544]
- NIH
- Swiss National Science Foundation (SNF) [310030_184720] Funding Source: Swiss National Science Foundation (SNF)
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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 aHER2 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.
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