Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic

Abstract

Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile prodrug of docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing malignancies. Here, we characterized the expression of EphA2 in bladder cancer using immunohistochemistry in 177 human bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with gemcitabine. EphA2 expression was detected in 80–100% of bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in tumor cells and/or tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing in all four EphA2-positive bladder cancer PDX models. Combination of EphA2-ILs-DTXp and gemcitabine in one PDX model led to improved tumor growth control compared to monotherapies or the combination of free docetaxel and gemcitabine. These data demonstrating the prevalence of EphA2 in bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in bladder cancer.

Targeted internalization and activation of glycosidic switch liposomes by an EphA2 PEG engager increases therapeutic efficacy against lung cancer

“…Antibody conjugation strategies for liposome modi cation without complicated chemical reactions may help translate targeted liposomes to the clinic. Walid et al developed immunoliposomes (MM-310) which encapsulate the hydrolysable docetaxel prodrug (DTXp) and engineered C-terminal cysteine residues into a EphA2 scFv to covalently attach the scFv to maleimide-terminated PEG-DSPE [54]. The antibodies were incorporated into liposomes by mixing MM-310 with anti-EphA2 scFv-PEG-DSPE at 60°C for 30 min.…”

A Sensitive Monoclonal Antibody B4Mab-7 against EphB4 Was Developed for Breast Cancers

“…Because Eph receptors are expressed in normal tissues and have important physiological functions, targeting them with conventional antibody drugs has been difficult. Therefore, recently, naked antibodies have been applied to chimeric antigen receptor-T cell therapy [107,108], ADC [87,88,99,109], bispecific T-cell engager [100,110], bispecific antibody [111,112], and liposomes [113], to target Eph receptors. Bispecific antibodies against EphA2/EphA3 reduced the clonogenicity of recurrent glioblastoma in vitro and the tumorigenic potential of xenograft recurrent glioblastoma in vivo [112].…”

Lipid Nanoparticles Functionalized with Antibodies for Anticancer Drug Therapy

“…A study [ 112 ] using multiple tumor-xenografted mice was the basis for initiating a phase 1 clinical trial (NCT03076372) to assess the safety and efficacy of MM-310 in multiple solid tumors. Kamoun et al [ 113 ] determined its preclinical efficacy in four ephrin A2-positive patient-derived xenograft models of bladder cancer, either as a monotherapy or in combination with GEM.…”