Molecular basis of antibody binding to mucin glycopeptides in lung cancer

Jin Qu, Hongtao Yu, Fenge Li, Chunlei Zhang, Ahmad Trad, Cory Brooks, Bin Zhang, Ting Gong, Zhi Guo, Yunsen Li, Govind Ragupathi, Yanyan Lou, Patrick Hwu, Wei Huang, Dapeng Zhou

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Glycopeptides bearing Tn epitopes are emerging targets for cancer diagnosis and immunotherapy. In this study, we analyzed membrane proteins containing O-glycosylated tandem repeat (TR) sequences in lung cancer patients of different types and stages, using gene microarray data in public domain. The expression of Tn and glycopeptide epitopes on the surface of lung cancer cell lines were studied by monoclonal IgG antibodies 14A, 16A, and B72.3. The binding of mAbs to synthetic glycopeptides were studied by surface plasmon resonance. Nine mucin mRNAs were found to be expressed in lung cancer patients but at similar level to healthy individuals. At protein level, a glycopeptide epitope on cancer cell surface is preferably recognized by mAb 16A, as compared to peptide-alone (14A) or sugar-alone epitopes (B72.3). 14A and 16A favor clustered TR containing more than three TR sequences, with 10-fold lower Kd than two consecutive TR. B72.3 preferrably recognized clustered sialyl-Tn displayed on MUC1 but not other O-glycoproteins, with 100-fold stronger binding when MUC1 is transfected as a sugar carrier, while the total sugar epitopes remain unchanged. These findings indicate that clusters of both TR backbones and sugars are essential for mAb binding to mucin glycopeptides. Three rules of antibody binding to mucin glycopeptides at molecular level are presented here: first, the peptide backbone of a glycopeptide is preferentially recognized by B cells through mutations in complementarity determining regions (CDRs) of B cell receptor, and the sugar-binding specificity is acquired through mutations in frame work of heavy chain; secondly, consecutive tandem repeats (TR) of peptides and glycopeptides are preferentially recognized by B cells, which favor clustered TR containing more than three TR sequences; thirdly, certain sugar-specific B cells recognize and accommodate clustered Tn and sialyl-Tn displayed on the surface of a mucin but not other membrane proteins.

Original languageEnglish (US)
Pages (from-to)587-594
Number of pages8
JournalInternational Journal of Oncology
Volume48
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Tandem Repeat Sequences
Glycopeptides
Mucins
Lung Neoplasms
Antibodies
Epitopes
B-Lymphocytes
Peptides
Membrane Proteins
Complementarity Determining Regions
Mutation
Surface Plasmon Resonance
Public Sector
Immunotherapy
Neoplasms
Glycoproteins
Immunoglobulin G
Monoclonal Antibodies
Cell Line
Messenger RNA

Keywords

  • Cancer biomarkers
  • Cancer vaccine
  • Glycopeptidome
  • Glycoproteome
  • Immunodiagnosis
  • Immunomonitoring
  • Immunotherapy
  • Lung cancer
  • Monoclonal antibody
  • Mucin
  • Sialyl-Tn antigen
  • Tn antigen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Qu, J., Yu, H., Li, F., Zhang, C., Trad, A., Brooks, C., ... Zhou, D. (2016). Molecular basis of antibody binding to mucin glycopeptides in lung cancer. International Journal of Oncology, 48(2), 587-594. https://doi.org/10.3892/ijo.2015.3302

Molecular basis of antibody binding to mucin glycopeptides in lung cancer. / Qu, Jin; Yu, Hongtao; Li, Fenge; Zhang, Chunlei; Trad, Ahmad; Brooks, Cory; Zhang, Bin; Gong, Ting; Guo, Zhi; Li, Yunsen; Ragupathi, Govind; Lou, Yanyan; Hwu, Patrick; Huang, Wei; Zhou, Dapeng.

In: International Journal of Oncology, Vol. 48, No. 2, 01.02.2016, p. 587-594.

Research output: Contribution to journalArticle

Qu, J, Yu, H, Li, F, Zhang, C, Trad, A, Brooks, C, Zhang, B, Gong, T, Guo, Z, Li, Y, Ragupathi, G, Lou, Y, Hwu, P, Huang, W & Zhou, D 2016, 'Molecular basis of antibody binding to mucin glycopeptides in lung cancer', International Journal of Oncology, vol. 48, no. 2, pp. 587-594. https://doi.org/10.3892/ijo.2015.3302
Qu, Jin ; Yu, Hongtao ; Li, Fenge ; Zhang, Chunlei ; Trad, Ahmad ; Brooks, Cory ; Zhang, Bin ; Gong, Ting ; Guo, Zhi ; Li, Yunsen ; Ragupathi, Govind ; Lou, Yanyan ; Hwu, Patrick ; Huang, Wei ; Zhou, Dapeng. / Molecular basis of antibody binding to mucin glycopeptides in lung cancer. In: International Journal of Oncology. 2016 ; Vol. 48, No. 2. pp. 587-594.
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