Open AccessTargeted glycan degradation potentiates the anticancer immune response in vivo
Author(s) -
Melissa A. Gray,
Michal A. Stanczak,
Natália Rodrigues Mantuano,
Han Xiao,
Johan F. A. Pijnenborg,
Stacy A. Malaker,
Caitlyn L. Miller,
Payton A. Weidenbacher,
Julia T. Tanzo,
Green Ahn,
Elliot C. Woods,
Heinz Läubli,
Carolyn R. Bertozzi
Publication year - 2020
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-020-0622-x
Subject(s) - siglec , cancer research , immune system , immune checkpoint , druggability , immunotherapy , cancer immunotherapy , downregulation and upregulation , kinome , cancer , immunology , biology , medicine , signal transduction , microbiology and biotechnology , biochemistry , gene
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.