Nucleic Acid Nanoparticle-based Monoclonal Antibody Mimics

Ball State University, Muncie IN

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Abstract

ABSTRACT Therapeutic monoclonal antibodies (mAbs) represent a rapidly expanding class of therapeutic agents, offering promise for treating various cancers, including prostate cancer (PC). However, their complex structure, elevated production cost, cross-reactivity, immunogenicity, and instability have limited their utilization in modern medicine and have prompted exploration for alternatives. Accordingly, nucleic acid aptamers, known for their high affinity and specificity (functions that mimic mAbs), have recently emerged as compelling substitutes in diagnostic, therapeutic, and targeting applications. By leveraging the advantages of aptamer technology and utilizing recently developed modular, enzymatically stable, and non-immunogenic chemically modified triangular nucleic acid nanoscaffold, a panel of highly stable next-gen NANPs capable of harboring numerous PC-binding aptamers in controlled manner will be constructed. This design will mirror the structural diversity of mAbs, including monomers (IgD, IgE, IgG), dimers (IgA), and pentamers (IgM). The enzymatically stable 2’F-modified RNA aptamer, recognized for its robust binding affinity to Prostate Specific Membrane Antigen (PSMA) on PC cells, stands as the primary aptamer candidate. In contrast to monoclonal mAbs, the resulting set of NANP-mAbs bypass the need for animal use in production. Also, compared to mAbs which require storage at -80 °C, the NANP-mAbs can be stored at room temperature for prolonged periods of time when dehydrated. Utilizing programmable NANPs synthesized and assembled in vitro ensures remarkable batch-to-batch consistency. Collectively these factors enable economical, highly accurate, and large-scale production of NANP-mAbs for both PC detection and treatment purposes. The long-term objective of this NIH AREA R15 proposal to develop next generation NANP-mAbs platform applicable to therapeutic interventions across various diseases and particular PC. The three Aims of this proposal are: 1. To construct and characterize next-gen NANP-mAbs assembled from stable and compact triangular nanoscaffolds; 2: To evaluate stability of the proposed NANP-mAbs in blood serum and study binding affinity to PSMA; and 3: To assess binding specificity of these NANPs-mAb to PC cells. The short term goal is to create a repertoire of nucleic acid-based nanoparticles capable of hosting multiple human PSMA binding aptamers along with an imaging dye, enabling synergistic and amplified PC-specific binding outcomes to be achieved. Binding affinities and cellular internalization of proposed set of next-gen NANP-mAbs will be rigorously compared and then screened for suitability in subsequent studies using in vivo models. Ultimately, the insights gathered from this innovative project will drive the development of robust Nucleic Acid Nanotechnology platforms with broad biomedical applications, aligning well with the mission of the National Institute of Biomedical Imaging and Bioengineering to "transform through technology development, our understanding of disease and its prevention, detection, diagnosis, and treatment."