Human xeno-autoantibodies against a non-human sialic acid serve as novel serum biomarkers and immunotherapeutics in cancer

Vered Padler-Karavani, Nancy Hurtado-Ziola, Minya Pu, Hai Yu, Shengshu Huang, Saddam Muthana, Harshal A. Chokhawala, Hongzhi Cao, Patrick Secrest, Dinorah Friedmann-Morvinski, Oded Singer, Darius Ghaderi, Inder M. Verma, Yu Tsueng Liu, Karen Messer, Xi Chen, Ajit Varki, Richard Schwab

Research output: Contribution to journalArticle

89 Scopus citations

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 Neu5Gca2α6GalNAcα1-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 complementdependent cytotoxicity or antibody-dependent cellular cytotoxicity. Such xeno-autoantibodies and xenoautoantigens have potential for novel diagnostics, prognostics, and therapeutics in human carcinomas.

Original languageEnglish (US)
Pages (from-to)3352-3363
Number of pages12
JournalCancer Research
Volume71
Issue number9
DOIs
StatePublished - May 1 2011

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Padler-Karavani, V., Hurtado-Ziola, N., Pu, M., Yu, H., Huang, S., Muthana, S., Chokhawala, H. A., Cao, H., Secrest, P., Friedmann-Morvinski, D., Singer, O., Ghaderi, D., Verma, I. M., Liu, Y. T., Messer, K., Chen, X., Varki, A., & Schwab, R. (2011). Human xeno-autoantibodies against a non-human sialic acid serve as novel serum biomarkers and immunotherapeutics in cancer. Cancer Research, 71(9), 3352-3363. https://doi.org/10.1158/0008-5472.CAN-10-4102