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.