Nucleic Acid Nanoparticle-based Monoclonal Antibody Mimics

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ABSTRACT Therapeutic monoclonal antibodies (mAbs) are the fastest growing class of new therapeutic agents. They hold great promise for the treatment of various types of cancer including prostate cancer (PC). However, their complex structure, selection difficulties, high costs of production, cross reactivity, immunogenicity, and relative instability are the major limitations in the rapidly evolving and demanding needs of modern medicine. Frequently compared to mAbs, Nucleic Acid (NA) aptamers bind with similarly high affinity and specificity to their epitopes and have recently emerged as attractive alternatives to mAbs in diagnostic, therapeutic, imaging and targeting applications. Herein, we propose to generate a panel of innovative nucleic acid-based nanoparticles (NANPs) that mimic mAbs (NANP-mAbs) by utilizing advantages of aptamers. Our recently developed modular, enzymatically stable, and non-immunogenic chemically modified nucleic acid polygons of different sizes and shapes will serve as scaffolds to harbor one or multiple PC binding aptamers at a precise position. The purpose of the programmed design is to mimic structural isotypes of mAbs including monomers (IgD, IgE, IgG), dimers (IgA), and pentamers (IgM). The enzymatically stable 2’F-modified RNA aptamer that is known to have strong binding affinity to Prostate Specific Membrane Antigen (PSMA) of PC cells is selected as primarily aptamer candidate. Unlike mAbs, the resulting NANP-mAbs do not require any animal use for their production and since programmable NANPs are synthesized and assembled in vitro, they offer a great batch-to-batch consistency. This all allows for an economical, highly accurate, large-scale production of the proposed NANP-mAbs for PC detection and treatment. The goal of this Academic Research Enhancement Award for Undergraduate-Focused Institutions (AREA) R15 proposal is to develop a robust NANP-mAbs system that can be used for therapeutic applications towards a broad range of diseases. The short-term objective is to construct a panel of NANP-mAbs that will accommodate multiple human PSMA binding aptamers and an imaging dye to generate synergistic and enhanced PC-specific binding and therapeutic effects. Binding affinities and cellular internalization of all NANP-mAbs will be systematically compared side-by-side and screen candidates for the in vivo models. Ultimately, the results generated from this innovative project will lead to the development of robust nanoscaffold platforms for biomedical applications.