Wednesday, January 15, 2025
1/15/2025
Project Summary: We have patented a novel polymer-based in vivo-delivery platform for therapeutic antibodies using a super- hydrophilic polymer, poly 2-methacryloyloxyethyl phosphorylcholine (PMPC) (US20220175857). This platform provides the following features to any antibodies tested: i) prolonged body circulation, ii) specific delivery irrespective of the target locations in the body, iii) protection from the environment and immune surveillance, and iv) selected release at specific locations upon response to the environment. In addition, this platform grants penetrable features to the central nervous system (CNS) and the lymph nodes (LNs), where antibody delivery is greatly challenging. Anti-cancer antibody directing CD20, rituximab, allowed for the complete elimination of systemically metastasized B-cell lymphomas, which are in the CNS and LNs, via engineering with this platform (nRTX). Moreover, animals treated with nRTX evoked a potent anti-cancer immune response through the efficient release of tumor-specific antigens within the LNs. Importantly, this platform has achieved the safe delivery of rituximab in mice, rats, and non-human primates. This year, nRTX has been selected as a collaborator project for the Nanotechnology Characterization Laboratory program toward its clinical translation. Very recently, we successfully simplified this platform for further smooth clinical translation using trastuzumab – a HER2-directing monoclonal antibody – without impairing most features listed above (provisional patent#: 63/579,586). The primary difference in this novel technology from the nanocapsule platform is to ensure the site-directed modification of antibodies by PMPC polymer without masking the epitope recognition capability and Fc-dependent antibody functions, such as antibody-dependent cellular cytotoxicity or Fc-receptor binding. We here applied this new platform to antibody-drug conjugates (ADCs) to improve their anti-cancer efficacy and overcome the known issues surrounding ADCs in clinical use. The site-specific PMPC engineering of ADCs allowed for heightening of the drug-antibody ratio (DAR) by two-fold compared to the parental ADC, Kadcyla (T- DM1), one of the HER2 directing ADCs approved by the FDA in 2013 to treat breast cancers. Moreover, this technology enabled exerting superior anti-cancer activity against various cancerous cells in comparison to Kadcyla, while providing the CNS-deliverable feature. Importantly, PMPC-engineering of Kadcyla with high DAR successfully induced anti-cancer immune responses without changes in adverse toxicity. Under this proposal, we will confirm the effectiveness of the site-directed PMPC-engineering of ADCs against other antigens selectively expressed on human cancer cells derived from different disease backgrounds. We will also test their efficacies in patient-derived xenograft mouse models. At the end, we will develop a novel ADC by further engineering the PMPC polymer structure to overcome therapy-resistant issues of ADC. These studies are intended to develop highly reliable, clinically relevant, and sufficiently safe ADCs.
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