Antibody directed nanotherapeutics represent a promising next generation antibody drug conjugate technology with several important characteristics.  First, the targeting ligand is only indirectly conjugated to the active drug payload through a nano-sized liposomal carrier and not covalently to the antibody itself.  Second, the liposomal nanocarrier of approximately 100-120 nm in size can encapsulate a sizeable payload of 20-150,000 drug molecules, allowing it to be applicable to a wide range of drugs with more standard potencies than observed for conventional ADCs.  The size of the nanocarrier also enables a second level of targeting due to the enhanced permeability and retention effect and its more restricted distribution into healthy tissues.  Here we demonstrate the potential of this platform through the engineering of an EphA2- antibody targeted nanotherapeutic encapsulating a novel docetaxel prodrug (MM-310).  MM-310 shows selective targeting of EphA2+ cancer cells and preferential uptake in solid tumors relative to an IgG Ab against EphA2 (C10).  The slow and sustained release of the docetaxel prodrug enables a limited systemic exposure to the active docetaxel and a dramatic reduction in neutropenia, the dose-limiting toxicity of free docetaxel.  The sustained tumor exposure results in a significant increase in antitumor activity in multiple xenograft tumor models compared to free docetaxel, and the ability to be more readily combined with a range of combination partners.  Finally, we describe the use of nano-sized imaging agents to predict the distribution and activity of both targeted and non-targeted nanotherapeutics.

Engineering and development of novel antibody-directed nanotherapeutics for the treatment of cancer

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.