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A collaborative research study in the framework of the European project GLYCOTwinning, led by researchers from UCIBIO-NOVA FCT and CIC BioGUNE revealed, for the first time, the molecular mechanism behind the binding of a specific antibody to a glycan-based antigen commonly found on malignant cells of some of the most difficult cancers to treat. The study was coordinated by Filipa Marcelo from (Bio)molecular Structure and Interactions by NMR Lab at UCIBIO-NOVA FCT and June Ereño-Orbea from CIC bioGUNE with important contribution of Paula Videira from Glycoimmunology Lab and Angelina Palma from GlycoLab at UCIBIO-NOVA, and the results were published recently in the Journal of American Chemical Society Au: “Decoding the Molecular Basis of the Specificity of an anti-sTn Antibody”. 

 

Glycans, sugar-based molecules that cover human cells, are crucial in cancer processes like cell signaling, invasion, and immune modulation. The sialyl Tn-antigen (sTn), a small glycan, is observed in many cancers, and is strongly associated with increased metastasis and poor outcomes, making it a key biomarker and therapeutic target. Developing specific, high-affinity monoclonal antibodies (mAbs) against sTn paves the way for innovative tools in cancer diagnosis and the development of new therapies. 

 

This article examines how structural biology techniques, such as NMR spectroscopy and X-ray crystallography, combined with computational methods, glycan/glycopeptide microarrays, and biophysical techniques disclose the binding mechanism of a pre-clinical anti-sTn antibody to the sTn antigen. 

 

In fact, this study provides, for the first time, the high-resolution information of sTn-antigen molecular recognition by an antibody. Key interactions between the sTn-antigen and the L2A5 antibody were unveiled, which might contribute to its selective targeting against tumour cells.  

 

"This newfound knowledge holds promise for the rational engineering of more effective antibodies for diagnosis and treatments for cancers expressing sTn-antigen, like breast, colorectal, and bladder cancer, improving patient care", concludes Filipa Marcelo.

 

Original article:  

Decoding the Molecular Basis of the Specificity of an Anti-sTn Antibody 

JACS Au 2024
Cátia O. Soares, Maria Elena Laugieri, Ana Sofia Grosso, Mariangela Natale, Helena Coelho, Sandra Behren, Jin Yu, Hui Cai, Antonio Franconetti, Iker Oyenarte, Maria Magnasco, Ana Gimeno, Nuno Ramos, Wengang Chai, Francisco Corzana, Ulrika Westerlind, Jesús Jiménez-Barbero, Angelina S. Palma, Paula A. Videira, June Ereño-Orbea, and Filipa Marcelo 

DOI: 10.1021/jacsau.4c00921