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Targeted Desialylation Overcomes Glyco-Immune Checkpoints and Potentiates the Anticancer Immune Response in Vivo

preprint
revised on 13.11.2019 and posted on 25.11.2019 by Melissa Gray, Michal A. Stanczak, Han Xiao, Johan F. A. Pijnenborg, Natália R. Mantuano, Stacy A. Malaker, Payton A. Weidenbacher, Caitlyn L. Miller, Julia T. Tanzo, Green Ahn, Elliot C. Woods, Heinz Läubli, Carolyn Bertozzi

Currently approved immune checkpoint inhibitor (ICI) therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, the majority of patients across cancer types still fail to respond. Addressing alternative pathways that mediate immune suppression could enhance ICI efficacy. One such mechanism is the increase in sialic acid-containing proteins and lipids (sialoglycans) in malignancy, which recently has been shown to inhibit immune cell activation through multiple mechanisms including Siglec receptor binding, and therefore represents a targetable glyco-immune checkpoint. Here, we report the design of a trastuzumab- sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells in vivo. In a syngeneic orthotopic HER2+ breast cancer model, targeted desialylation delayed tumor growth and enhanced immune cell infiltration and activation, leading to prolonged survival of mice with trastuzumab-resistant breast cancer. Thus, antibody-sialidase conjugates represent a promising modality for cancer immune therapy.

Funding

NIH CA227942

History

Email Address of Submitting Author

bertozzi@stanford.edu

Institution

Stanford University

Country

USA

ORCID For Submitting Author

0000-0003-4482-2754

Declaration of Conflict of Interest

M.A.G, H.X., E.C.W., and C.R.B., are inventors of the patent filed by Stanford University (international publication number WO2018006034A1) titled “Conjugates for targeted cell-surface editing” published on January 4, 2018 and licensed by Palleon Pharmaceuticals on 06/27/2017. C.R.B. is a co-founder and Scientific Advisory Board member of Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent) and InterVenn Biosciences, and a member of the Board of Directors of Eli Lilly & Company. H.L. received research and traveling support from Bristol-Myers Squibb. H.L. received traveling support from Merck Sharp Dome and Roche. H.L. is a member of the Scientific Advisory Board of Palleon Pharmaceuticals.

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