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Mol Cancer Ther. 2020 Mar;19(3):790-801. doi: 10.1158/1535-7163.MCT-19-0221. Epub 2019 Dec 23.

Monoclonal Antibody Targeting Sialyl-di-Lewisa-Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential.

Author information

1
Division of Cancer and Stem Cells, School of Medicine, City Hospital Campus, University of Nottingham, Nottingham, United Kingdom.
2
Scancell Limited, University of Nottingham Biodiscovery Institute, Nottingham, United Kingdom.
3
Section of Surgery, School of Medicine, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
4
Division of Cancer and Stem Cells, School of Medicine, City Hospital Campus, University of Nottingham, Nottingham, United Kingdom. lindy.durrant@nottingham.ac.uk.

Abstract

Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal cancer therapy. FG129, obtained through BALB/c mouse immunizations with liposomes containing membrane glycan extracts from the colorectal cancer cell line LS180, is an mIgG1κ that targets sialyl-di-Lewisa-containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, binds with nanomolar functional affinity to a range of colorectal, pancreatic, and gastric cancer cell lines. FG129 targets 74% (135/182) of pancreatic, 50% (46/92) of gastric, 36% (100/281) of colorectal, 27% (89/327) of ovarian, and 21% (42/201) of non-small cell lung cancers, by IHC. In our pancreatic cancer cohort, high FG129 glyco-epitope expression was significantly associated with poor prognosis (P = 0.004). Crucially, the glyco-epitope displays limited normal tissue distribution, with FG129 binding weakly to a small percentage of cells within gallbladder, ileum, liver, esophagus, pancreas, and thyroid tissues. Owing to glyco-epitope internalization, we validated payload delivery by CH129 through monomethyl auristatin E (MMAE) or maytansinoid (DM1 and DM4) conjugation. All three CH129 drug conjugates killed high-binding colorectal and pancreatic cancer cell lines with (sub)nanomolar potency, coinciding with significant in vivo xenograft tumor control by CH129-vcMMAE. CH129, with its restricted normal tissue distribution, avid tumor binding, and efficient payload delivery, is a promising candidate for the treatment of sialyl-di-Lewisa-expressing solid tumors, as an antibody-drug conjugate or as an alternative cancer immunotherapy modality.

PMID:
31871270
DOI:
10.1158/1535-7163.MCT-19-0221
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