Design and development of synthetic nanoparticle antibodies to deplete selected target cells for cancer immunotherapy
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Monoclonal antibodies (mAbs) have shown great promise as immunotherapy of cancer in the past decades. They mediate the antibody-dependent immune responses to eliminate the malignant or suppressive cells and proteins and restore anti-cancer immunity. However, the application of monoclonal antibodies as therapeutics is greatly hampered by its high production cost as well as high dosage required to generate significant therapeutic effect due to limited tissue penetration and retention. Additionally, monoclonal antibodies targeting some important immunological targets, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells, are still waiting to be developed. Here, we have developed a novel type of artificial antibodies, the synthetic nanoparticle antibodies (SNAbs), which are Janus nanoparticles multivalently displaying both binding ligands for the selected cellular targets and Fc-mimicking ligands that can activate Fc receptors. Our primary hypothesis is that the designed SNAbs could induce antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP) of cellular targets efficiently both in vitro and in vivo. A simple chemistry to fabricate Janus gold nanoparticles and to modify these nanoparticles with peptide ligands was designed to generate SNAbs. We evaluated the capability of SNAbs to target MDSCs, as a model cell type in both ex vivo assays and in vivo tumor model systems. We showed that SNAbs can selectively induce the antibody-dependent killing of MDSCs in the mixture of various types of cells and are also able to deplete MDSCs in a tumor model. The research completed in this thesis demonstrated that the SNAbs are a functional alternative to monoclonal antibodies and hold great promise as a potent immunotherapy for cancer.