title: Human xeno-autoantibodies against a non-human sialic acid serve as novel serum biomarkers and immunotherapeutics in cancer.
abstract: Human carcinomas can metabolically incorporate and present the dietary non-human sialic acid Neu5Gc, which differs from the human sialic acid N-acetylneuraminic acid (Neu5Ac) by 1 oxygen atom. Tumor-associated Neu5Gc can interact with low levels of circulating anti-Neu5Gc antibodies, thereby facilitating tumor progression via chronic inflammation in a human-like Neu5Gc-deficient mouse model. Here we show that human anti-Neu5Gc antibodies can be affinity-purified in substantial amounts from clinically approved intravenous IgG (IVIG) and used at higher concentrations to suppress growth of the same Neu5Gc-expressing tumors. Hypothesizing that this polyclonal spectrum of human anti-Neu5Gc antibodies also includes potential cancer biomarkers, we then characterize them in cancer and noncancer patients' sera, using a novel sialoglycan microarray presenting multiple Neu5Gc-glycans and control Neu5Ac-glycans. Antibodies against Neu5Gcα2-6GalNAcα1-O-Ser/Thr (GcSTn) were found to be more prominent in patients with carcinomas than with other diseases. This unusual epitope arises from dietary Neu5Gc incorporation into the carcinoma marker Sialyl-Tn, and is the first example of such a novel mechanism for biomarker generation. Finally, human serum or purified antibodies rich in anti-GcSTn-reactivity kill GcSTn-expressing human tumors via complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. Such xeno-autoantibodies and xeno-autoantigens have potential for novel diagnostics, prognostics, and therapeutics in human carcinomas.
authors.affiliation: University of California at San Diego, CA, USA.
authors.forename: Vered
authors.initials: V
authors.lastname: Padler-Karavani
authors.forename: Nancy
authors.initials: N
authors.lastname: Hurtado-Ziola
authors.forename: Minya
authors.initials: M
authors.lastname: Pu
authors.forename: Hai
authors.initials: H
authors.lastname: Yu
authors.forename: Shengshu
authors.initials: S
authors.lastname: Huang
authors.forename: Saddam
authors.initials: S
authors.lastname: Muthana
authors.forename: Harshal A
authors.initials: HA
authors.lastname: Chokhawala
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Cao
authors.forename: Patrick
authors.initials: P
authors.lastname: Secrest
authors.forename: Dinorah
authors.initials: D
authors.lastname: Friedmann-Morvinski
authors.forename: Oded
authors.initials: O
authors.lastname: Singer
authors.forename: Darius
authors.initials: D
authors.lastname: Ghaderi
authors.forename: Inder M
authors.initials: IM
authors.lastname: Verma
authors.forename: Yu-Tsueng
authors.initials: YT
authors.lastname: Liu
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Ajit
authors.initials: A
authors.lastname: Varki
authors.forename: Richard
authors.initials: R
authors.lastname: Schwab
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000276:immunology / Q000628:therapy; D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000276:immunology; D001943:Breast Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy; D003110:Colonic Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D007074:Immunoglobulin G / Q000276:immunology / Q000302:isolation & purification; D016756:Immunoglobulins, Intravenous / Q000737:chemistry / Q000276:immunology; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D019158:N-Acetylneuraminic Acid / Q000276:immunology*; D009369:Neoplasms / Q000097:blood* / Q000276:immunology / Q000628:therapy*
chemical_list: D001323:Autoantibodies; D014408:Biomarkers, Tumor; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D019158:N-Acetylneuraminic Acid