TY - JOUR
T1 - Human xeno-autoantibodies against a non-human sialic acid serve as novel serum biomarkers and immunotherapeutics in cancer
AU - Padler-Karavani, Vered
AU - Hurtado-Ziola, Nancy
AU - Pu, Minya
AU - Yu, Hai
AU - Huang, Shengshu
AU - Muthana, Saddam
AU - Chokhawala, Harshal A.
AU - Cao, Hongzhi
AU - Secrest, Patrick
AU - Friedmann-Morvinski, Dinorah
AU - Singer, Oded
AU - Ghaderi, Darius
AU - Verma, Inder M.
AU - Liu, Yu Tsueng
AU - Messer, Karen
AU - Chen, Xi
AU - Varki, Ajit
AU - Schwab, Richard
PY - 2011/5/1
Y1 - 2011/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955488798&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-10-4102
DO - 10.1158/0008-5472.CAN-10-4102
M3 - مقالة
SN - 0008-5472
VL - 71
SP - 3352
EP - 3363
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -
