Monoclonal Antibodies Targeting LecLex-Related Glycans with Potent Anti-Tumor Activity
Menée in vitro et in vivo, cette étude identifie deux anticorps monoclonaux ciblant des glycanes, puis met en évidence leur activité antitumorale dans un modèle de tumeur métastatique colorectale
Purpose:To produce anti-tumor monoclonal antibodies (mAbs) targetting glycans as they are aberrantly expressed in tumors and are co-accessory molecules for key survival pathways. Experimental Design:Two mAbs (FG88.2 and FG88.7) recognizing novel tumor-associated lewis (Le) glycans were produced by immunizations with plasma membrane lipid extracts of the COLO205 cell line. Results:: Glycan array analysis showed that both mAbs bound LecLex, di-Lea, and LeaLex, as well as Lea-containing glycans. These glycans are expressed on both lipids and proteins. Both mAbs showed strong tumor reactivity, binding to 71% (147/208) of colorectal, 81% (155/192) of pancreatic, 54% (52/96) of gastric, 23% (62/274) of non-small cell lung and 31% (66/217) of ovarian tumor tissue in combination with a restricted normal tissue distribution. In colorectal cancer, high FG88 glyco-epitope expression was significantly associated with poor survival. The mAbs demonstrated excellent antibody dependent cellular cytotoxicity (ADCC) and complement-mediated lysis (CDC), in addition to direct tumor cell killing via a caspase-independent mechanism. Scanning electron microscopy revealed antibody-induced pore formation. Additionally, the mAbs internalized, co-localized with lysosomes and delivered saporin which killed cells with sub-nanomolar potency. In vivo, the mAbs demonstrated potent anti-tumor efficacy in a metastatic colorectal tumor model, leading to significant long term survival. Conclusions:The mAbs direct and immune-assisted tumor cell killing, pan-tumor reactivity and potent in vivo anti-tumor efficacy indicates their potential as therapeutic agents for the treatment of multiple solid tumors. Additionally, internalization of saporin conjugates and associated tumor cell killing suggests their potential as antibody drug carriers.