Biomolecular recognition of the glycan neoantigen CA19-9 by distinct antibodies

ABSTRACT Glycans decorate cell surface, secreted glycoproteins and glycolipids. Altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potentials, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity bi...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Borenstein-Katz, Aliza, Warszawski, Shira, Amon, Ron, Nova Tasnima, Yu, Hai, Chen, Xi, Padler-Karavani, Vered, Sarel Jacob Fleishman, Diskin, Ron
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 17.02.2021
Subjects
Affinity
Antibodies
Antigens
Cell surface
Computer applications
Crystallography
Glycolipids
Glycoproteins
Neoantigens
Patent applications
Polysaccharides
X-ray crystallography
Online AccessGet full text

Cover

More Information
Summary:ABSTRACT Glycans decorate cell surface, secreted glycoproteins and glycolipids. Altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potentials, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity binding antibodies. To understand the mechanisms by which glycan neoantigens are specifically recognized by antibodies, we analyze the biomolecular recognition of a single tumor-associated carbohydrate antigen CA19-9 by two distinct antibodies using X-ray crystallography. Despite the plasticity of glycans and the very different antigen-binding surfaces presented by the antibodies, both structures reveal an essentially identical extended CA19-9 conformer, suggesting that this conformer’s stability selects the antibodies. Starting from the bound structure of one of the antibodies, we use the AbLIFT computational method to design a variant with seven core mutations that exhibited tenfold improved affinity for CA19-9. The results reveal strategies used by antibodies to specifically recognize glycan antigens and show how automated antibody-optimization methods may be used to enhance the clinical potential of existing antibodies. Competing Interest Statement The Weizmann Institute of Science, together with Tel-Aviv University, filed a patent application for AbLIFT-15.
DOI:10.1101/2021.02.17.431565