title: Precision glycocalyx editing as a strategy for cancer immunotherapy.
abstract: Cell surface sialosides constitute a central axis of immune modulation that is exploited by tumors to evade both innate and adaptive immune destruction. Therapeutic strategies that target tumor-associated sialosides may therefore potentiate antitumor immunity. Here, we report the development of antibody-sialidase conjugates that enhance tumor cell susceptibility to antibody-dependent cell-mediated cytotoxicity (ADCC) by selective desialylation of the tumor cell glycocalyx. We chemically fused a recombinant sialidase to the human epidermal growth factor receptor 2 (HER2)-specific antibody trastuzumab through a C-terminal aldehyde tag. The antibody-sialidase conjugate desialylated tumor cells in a HER2-dependent manner, reduced binding by natural killer (NK) cell inhibitory sialic acid-binding Ig-like lectin (Siglec) receptors, and enhanced binding to the NK-activating receptor natural killer group 2D (NKG2D). Sialidase conjugation to trastuzumab enhanced ADCC against tumor cells expressing moderate levels of HER2, suggesting a therapeutic strategy for cancer patients with lower HER2 levels or inherent trastuzumab resistance. Precision glycocalyx editing with antibody-enzyme conjugates is therefore a promising avenue for cancer immune therapy.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-4404; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-4404.
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-4404; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-4404.
authors.forename: Elliot C
authors.initials: EC
authors.lastname: Woods
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-4404; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-4404.
authors.forename: Petar
authors.initials: P
authors.lastname: Vukojicic
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-4404; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305-4404 bertozzi@stanford.edu.
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Bertozzi
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D019276:Glycocalyx / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D009439:Neuraminidase / Q000008:administration & dosage / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000276:immunology; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000235:genetics* / Q000276:immunology; D000068878:Trastuzumab / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D055655:NK Cell Lectin-Like Receptor Subfamily K; D009439:Neuraminidase; D018719:Erb-b2 Receptor Tyrosine Kinases; D063267:Sialic Acid Binding Ig-like Lectin 1; D000068878:Trastuzumab; C571166:SIGLEC1 protein, human; C508053:ERBB2 protein, human
keywords: ADCC; Siglec; cancer immune therapy; sialic acid; trastuzumab