Development of Therapeutic Anti-JAGGED1 Antibodies for Cancer Therapy.

Molecular Cancer Therapeutics
Massimo MasieroAlison H Banham

Abstract

The role of Notch signaling and its ligand JAGGED1 (JAG1) in tumor biology has been firmly established, making them appealing therapeutic targets for cancer treatment. Here, we report the development and characterization of human/rat-specific JAG1-neutralizing mAbs. Epitope mapping identified their binding to the Notch receptor interaction site within the JAG1 Delta/Serrate/Lag2 domain, where E228D substitution prevented effective binding to the murine Jag1 ortholog. These antibodies were able to specifically inhibit JAG1-Notch binding in vitro, downregulate Notch signaling in cancer cells, and block the heterotypic JAG1-mediated Notch signaling between endothelial and vascular smooth muscle cells. Functionally, in vitro treatment impaired three-dimensional growth of breast cancer cell spheroids, in association with a reduction in cancer stem cell number. In vivo testing showed variable effects on human xenograft growth when only tumor-expressed JAG1 was targeted (mouse models) but a more robust effect when stromal-expressed Jag1 was also targeted (rat MDA-MB-231 xenograft model). Importantly, treatment of established triple receptor-negative breast cancer brain metastasis in rats showed a significant reduction in neoplastic gr...Continue Reading

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Citations

Sep 17, 2020·Cancers·Maria Teresa PalanoRaffaella Chiaramonte
Apr 4, 2021·Cells·Catia GiovanniniLaura Gramantieri
Apr 30, 2021·Frontiers in Immunology·Panagiotis F ChristopoulosEirik Sundlisæter
May 11, 2021·Journal of Biomedical Science·Angelo Giuseppe CondorelliDaniele Castiglia
Jul 1, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Meng-Xi XiuBo-Hai Kuang

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