A Novel Monoclonal Antibody Targeting Cancer-Specific Plectin Has Potent Antitumor Activity in Ovarian Cancer

Abstract

Cancer-specific plectin (CSP) is a pro-tumorigenic protein selectively expressed on the cell surface of major cancers, including ovarian cancer (OC). Despite its assessable localization, abundance, and functional significance, the therapeutic efficacy of targeting CSP remains unexplored. Here, we generated and investigated the anticancer effects of a novel CSP-targeting monoclonal antibody, 1H11, in OC models. Its therapeutic efficacy as a monotherapy and in combination with chemotherapy was evaluated in vitro using two OC cell lines and in vivo by a subcutaneous ovarian cancer model. 1H11 demonstrated rapid internalization and high affinity and specificity for both human and murine CSP. Moreover, 1H11 induced significant and selective cytotoxicity (EC50 = 260 nM), G0/G1 arrest, and decreased OC cell migration. Mechanistically, these results are associated with increased ROS levels and reduced activation of the JAK2-STAT3 pathway. In vivo, 1H11 decreased Ki67 expression, induced 65% tumor growth inhibition, and resulted in 30% tumor necrosis. Moreover, 1H11 increased chemosensitivity to cisplatin resulting in 60% greater tumor growth inhibition compared to cisplatin alone. Taken together, CSP-targeting with 1H11 exhibits potent anticancer activity against ovarian cancer and is deserving of future clinical development.

Plectin in Cancer: From Biomarker to Therapeutic Target

“…Consistently, in vivo treatment with 1H11 induced sustained tumor growth inhibition and resulted in 30% tumor necrosis compared to the IgG control group. IHC analysis of tumor tissue revealed 1H11 inhibited cell proliferation, resulting in decreased Ki67 and increased p21 staining [98]. CSP inhibition recapitulated the anti-cancer effects seen from plectin knockout studies, seemingly implicating CSP as a potent mediator of plectin's protumorigenic function.…”

“…Similarly, the overexpression of plectin-1a and -1f isoforms was also revealed to induce CSP expression on cancer cells previously devoid of CSP [12]. Moreover, a recent study by Perez et al implemented a pharmacologic approach to investigating CSP's function in ovarian cancer [98]. A first-in-class CSP-targeting monoclonal antibody, 1H11, was shown to internalize without interacting with intracellular plectin, thus inducing CSP-specific targeted consequences.…”

“…Strikingly, 1H11 was shown to synergize with current mainstay therapies, including cisplatin, olaparib, and doxorubicin. In vivo, dual treatment of 1H11 and cisplatin resulted in 60% greater tumor growth inhibition than cisplatin alone [98]. Taken together, Perez et al are the first to expand on and marshal our understanding of CSP as a valuable therapeutic target.…”

“…Currently, there are only about two dozen cell-surface proteins targeted by approved therapeutic antibodies, underscoring the need to widen our cell-surface antigen repertoire [127]. In a recent study featured in this Cells Special Issue, Perez et al developed a first-in-class anti-CSP monoclonal antibody, 1H11, that binds to CSP-positive cells with high affinity and specificity, after which it triggers rapid internalization and sequestering of 1H11 to vesicles [98]. In vitro, 1H11 selectively induced cytotoxicity, G0/G1 arrest, and decreased cell migration in CSP-positive ovarian cancer cells, OVCAR8 and SKOV3, but not healthy fallopian tube cells (FT132) [98].…”

“…In a recent study featured in this Cells Special Issue, Perez et al developed a first-in-class anti-CSP monoclonal antibody, 1H11, that binds to CSP-positive cells with high affinity and specificity, after which it triggers rapid internalization and sequestering of 1H11 to vesicles [98]. In vitro, 1H11 selectively induced cytotoxicity, G0/G1 arrest, and decreased cell migration in CSP-positive ovarian cancer cells, OVCAR8 and SKOV3, but not healthy fallopian tube cells (FT132) [98]. These observations were associated with inhibition of the JAK2-STAT3 pathway, upregulation of cyclin-dependent kinase inhibitors, p21 and p27, and differential expression of EMT markers E-cadherin and vimentin.…”