Molecular and structural basis for Lewis glycan recognition by a cancer-targeting antibody

Caroline Soliman, Andrew J. Guy, Jia Xin Chua, Mireille Vankemmelbeke, Richard S. McIntosh, Sarah Eastwood, Vi Khanh Truong, Aaron Elbourne, Ian Spendlove, Lindy G. Durrant, Paul A. Ramsland

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Immunotherapy has been successful in treating many tumour types. The development of additional tumour-antigen binding monoclonal antibodies (mAbs) will help expand the range of immunotherapeutic targets. Lewis histo-blood group and related glycans are overexpressed on many carcinomas, including those of the colon, lung, breast, prostate and ovary, and can therefore be selectively targeted by mAbs. Here we examine the molecular and structural basis for recognition of extended Leaand Lexcontaining glycans by a chimeric mAb. Both the murine (FG88.2) IgG3 and a chimeric (ch88.2) IgG1 mAb variants showed reactivity to colorectal cancer cells leading to significantly reduced cell viability. We determined the X-ray structure of the unliganded ch88.2 fragment antigenbinding (Fab) containing two Fabs in the unit cell. A combination of molecular docking, glycan grafting and molecular dynamics simulations predicts two distinct subsites for recognition of Leaand Lextrisaccharides. While light chain residues were exclusively used for Leabinding, recognition of Lexinvolved both light and heavy chain residues. An extended groove is predicted to accommodate the Lea-Lex hexasaccharide with adjoining subsites for each trisaccharide. The molecular and structural details of the ch88.2 mAb presented here provide insight into its cross-reactivity for various Lea and Lex containing glycans. Furthermore, the predicted interactions with extended epitopes likely explains the selectivity of this antibody for targeting Lewis-positive tumours.

Original languageEnglish
Pages (from-to)3219-3235
Number of pages17
JournalBiochemical Journal
Volume477
Issue number17
DOIs
Publication statusPublished - Sep 2020
Externally publishedYes

Keywords

  • Molecular
  • Lewis Glycan Recognition
  • Cancer

Fingerprint

Dive into the research topics of 'Molecular and structural basis for Lewis glycan recognition by a cancer-targeting antibody'. Together they form a unique fingerprint.

Cite this