A strategy for generating cancer-specific monoclonal antibodies to aberrant O-glycoproteins: identification of a novel dysadherin-Tn antibody

TY - JOUR

T1 - A strategy for generating cancer-specific monoclonal antibodies to aberrant O-glycoproteins

T2 - identification of a novel dysadherin-Tn antibody

AU - Steentoft, Catharina

AU - Fuhrmann, Max

AU - Battisti, Federico

AU - Van Coillie, Julie

AU - Madsen, Thomas D

AU - Campos, Diana

AU - Halim, Adnan

AU - Vakhrushev, Sergey Y

AU - Joshi, Hiren

AU - Schreiber, Hans

AU - Mandel, Ulla

AU - Narimatsu, Yoshiki

PY - 2019/2/6

Y1 - 2019/2/6

N2 - O-glycosylated proteins contain promising cancer-specific O-glycopeptide epitopes suitable for immunotherapeutic applications, but currently only few examples of such antibody epitopes have been identified. We previously showed that chimeric antigen receptor T-cells directed towards aberrantly O-glycosylated MUC1 can control malignant growth in a mouse model. Here, we present a discovery platform for the generation of cancer-specific monoclonal antibodies targeting aberrant O-glycoproteins. The strategy is based on cancer cell lines engineered to homogeneously express the truncated Tn O-glycoform, the so-called SimpleCells. We used SimpleCells of different cancer origin to elicit monoclonal antibodies with selectivity for aberrant O-glycoproteins. For validation we selected and characterized one monoclonal antibody (6C5) directed to a Tnglycopeptide in dysadherin (FXYD5), known to be upregulated in cancer and promote metastasis. While dysadherin is widely expressed also in normal cells, we demonstrated that the 6C5 epitope is specifically expressed in cancer.

AB - O-glycosylated proteins contain promising cancer-specific O-glycopeptide epitopes suitable for immunotherapeutic applications, but currently only few examples of such antibody epitopes have been identified. We previously showed that chimeric antigen receptor T-cells directed towards aberrantly O-glycosylated MUC1 can control malignant growth in a mouse model. Here, we present a discovery platform for the generation of cancer-specific monoclonal antibodies targeting aberrant O-glycoproteins. The strategy is based on cancer cell lines engineered to homogeneously express the truncated Tn O-glycoform, the so-called SimpleCells. We used SimpleCells of different cancer origin to elicit monoclonal antibodies with selectivity for aberrant O-glycoproteins. For validation we selected and characterized one monoclonal antibody (6C5) directed to a Tnglycopeptide in dysadherin (FXYD5), known to be upregulated in cancer and promote metastasis. While dysadherin is widely expressed also in normal cells, we demonstrated that the 6C5 epitope is specifically expressed in cancer.

U2 - 10.1093/glycob/cwz004

DO - 10.1093/glycob/cwz004

M3 - Journal article

C2 - 30726901

SN - 0959-6658

VL - 29

SP - 307

EP - 319

JO - Glycobiology

JF - Glycobiology

IS - 4

ER -