Antitumour activity and tolerability of an EphA2-targeted nanotherapeutic in multiple mouse models

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

“…EphA2-ILs-DTXp was prepared as described by Kamoun [ 30 ]. Briefly, the anti-EphA2 scFv protein 310-24 scFv was expressed in mammalian cell culture, purified by protein-A affinity chromatography, and conjugated through an engineered C-terminal cysteine residue to the maleimide-terminated lipopolymer, mal-PEG-DSPE.…”

“…These properties make EphA2 a promising candidate for the development of targeted cytotoxic drugs. Several EphA2-targeted agents that aimed to deliver cytotoxic molecules were developed including antibody drug conjugates (ADCs) [ 27 ], agonist peptide-drug conjugates [ 28 , 29 ], and targeted-nanotherapeutics [ 30 ]. While these studies provided evidence of enhanced preclinical in vivo activity in primary and metastatic cancer models, mechanisms linking EphA2-targeting with increased efficacy were not fully elucidated.…”

“…Moreover, the only EphA2-targeted ADC that reached the clinical phase of development, MEDI-547, showed significant toxicities in its phase 1 trial, limiting its therapeutic index and clinical development [ 27 ]. We have recently developed a novel EphA2-targeted antibody directed nanotherapeutic (ADN), named EphA2-ILs-DTXp (MM-310), which encapsulates a hydrolytically sensitive prodrug of docetaxel (DTXp) [ 30 ]. EphA2-ILs-DTXp was engineered to have advantageous pharmacokinetic properties, resulting in decreased plasma exposure to DTX while maintaining selective tumor exposure [ 30 ].…”

“…We have recently developed a novel EphA2-targeted antibody directed nanotherapeutic (ADN), named EphA2-ILs-DTXp (MM-310), which encapsulates a hydrolytically sensitive prodrug of docetaxel (DTXp) [ 30 ]. EphA2-ILs-DTXp was engineered to have advantageous pharmacokinetic properties, resulting in decreased plasma exposure to DTX while maintaining selective tumor exposure [ 30 ]. Preclinical studies suggest that EphA2-targeting contributes to EphA2-ILs-DTXp activity primarily through a shift in the microdistribution of the drug, resulting in increased tumor area drug exposure [ 30 ].…”

“…EphA2-ILs-DTXp was engineered to have advantageous pharmacokinetic properties, resulting in decreased plasma exposure to DTX while maintaining selective tumor exposure [ 30 ]. Preclinical studies suggest that EphA2-targeting contributes to EphA2-ILs-DTXp activity primarily through a shift in the microdistribution of the drug, resulting in increased tumor area drug exposure [ 30 ].…”