RT Journal Article
SR Electronic
T1 Monoclonal Antibody Targeting Sialyl-di-Lewisa - Containing Internalizing and non-Internalizing Glycoproteins with Cancer Immunotherapy Development Potential
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP molcanther.0221.2019
DO 10.1158/1535-7163.MCT-19-0221
A1 Tivadar, Silvana T
A1 McIntosh, Richard S
A1 Chua, Jia Xin
A1 Moss, Robert
A1 Parsons, Tina
A1 Zaitoun, Abed M.
A1 Madhusudan, Srinivasan
A1 Durrant, Lindy G
A1 Vankemmelbeke, Mireille
YR 2019
UL http://mct.aacrjournals.org/content/early/2019/12/21/1535-7163.MCT-19-0221.abstract
AB 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 monoclonal antibody, 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 a mIgG1ƙ, that targets sialyl-di-Lewisa-containing glycoproteins. FG129, as well as its chimeric human IgG1 variant, CH129, bind 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 immunohistochemistry. 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, oesophagus, 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 ADC or as an alternative cancer immunotherapy modality.