A Novel Antibody-Drug Conjugate Targeting Nectin-2 Suppresses Ovarian Cancer Progression in Mouse Xenograft Models

Abstract

Ovarian cancer is the fifth leading cause of cancer, followed by front line is mostly platinum agents and PARP inhibitors, and very limited option in later lines. Therefore, there is a need for alternative therapeutic options. Nectin-2, which is overexpressed in ovarian cancer, is a known immune checkpoint that deregulates immune cell function. In this study, we generated a novel anti-nectin-2 antibody (chimeric 12G1, c12G1), and further characterized it using epitope mapping, enzyme-linked immunosorbent assay, surface plasmon resonance, fluorescence-activated cell sorting, and internalization assays. The c12G1 antibody specifically bound to the C2 domain of human nectin-2 with high affinity (KD = 2.90 × 10−10 M), but not to mouse nectin-2. We then generated an antibody-drug conjugate comprising the c12G1 antibody conjugated to DM1 and investigated its cytotoxic effects against cancer cells in vitro and in vivo. c12G1-DM1 induced cell cycle arrest at the mitotic phase in nectin-2-positive ovarian cancer cells, but not in nectin-2-negative cancer cells. c12G1-DM1 induced ~100-fold cytotoxicity in ovarian cancer cells, with an IC50 in the range of 0.1 nM~7.4 nM, compared to normal IgG-DM1. In addition, c12G1-DM1 showed ~91% tumor growth inhibition in mouse xenograft models transplanted with OV-90 cells. These results suggest that c12G1-DM1 could be used as a potential therapeutic agent against nectin-2-positive ovarian cancers.

Serum immune mediators as novel predictors of response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer patients with high tissue-PD-L1 expression

“…Nectin-2 is a immunoglobulin-like cell-to-cell adhesion protein that acts in a stimulatory or inhibitory manner Several studies on serum Nectin-2 have associated its overexpression with aggressiveness and metastasis in various cancers including colon, breast, esophageal and lung indicating its role as a prognostic and predictive biomarker in cancers (73)(74)(75)(76). Moreover, blockade via anti-Nectin-2 monoclonal antibodies can induce antibodydependent cellular cytotoxicity (ADCC) with robust anti-tumor response in breast and ovarian cancers, indicating its role in immune regulation (77,78). Similar results were observed for Esophageal squamous cell carcinoma (ESCC) where knockdown of Nectin−2 in ESCC cell lines was associated with effective suppression of cell migration and invasion (75).…”

Single cell analysis of epithelial, immune, and stromal signatures and interactions in human ovarian cancer

“…Our study identi ed NECTIN2, the ligand gene that most interacts with TIGIT. Nectin-2 is an adhesion molecule, has reported as a potential antibody therapy target, suppressed OC progression in mouse models 43,44 . This result suggested nectin-2 is also a potential target of immune checkpoint inhibitors therapy of OC.…”

Future theranostic strategies: emerging ovarian cancer biomarkers to bridge the gap between diagnosis and treatment

“…VEGF stimulates nectin-2 expression leading to indirect regulation of endothelial cells (Bekes et al, 2019). A chimeric anti-nectin-2 antibody (c12G1) has been conjugated to a cytotoxic drug to demonstrate significant anti-tumor activity in ovarian cancer models (Sim et al, 2022). Another family member, nectin-4, is overexpressed in ovarian cancer tissue (Nabih et al, 2014) and plays a role in tumor cell proliferation, motility, and invasion.…”