Aptamers are increasing being utilized in all phases of the drug discovery and development process. In some cases, aptamers offer enhanced functionality versus traditional antibodies. In other cases, aptamers offer accelerated time-to market, improved manufacturability, simplified regulatory requirements, and/or cost savings. Base Pair is currently working on several therapeutic aptamer projects.
Aptamers can be applied to a full range of analysis techniques which have traditionally utilized antibodies. Aptamers are easily modified in many ways, offering unique immobilization, conjugation and detection options. Utilization of aptamers can prevent non-specific binding due to rheumatoid factor, heterophilic antibodies and anti-animal antibodies sometimes present in patient samples. Structure-switching aptamers enable near-instant detection of critical targets in complex samples.
Because aptamers can be selected for binding to small molecules and toxic compounds, aptamers are ideal for use in bioanalysis and ADME/Tox studies. The ability of aptamers to infiltrate tissues / cells and specifically bind unique cell-surface markers makes them strong candidates for therapeutic agents and drug delivery agents.
Due to simple chemical synthesis, the application of aptamers in drug manufacturing and purification decreases cost and complexity, improves batch to batch consistency, and guarantees long-term availability.
Aptamer discovery and development can potentially decrease time to market when compared to traditional antibody reagents and therapeutics. Aptamers with selective binding and structure-switching capability offer new options in diagnostics and therapeutics. Implementation of aptamers in manufacturing can reduce manufacturing costs and production time in competitive markets.
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Identifying, detecting, and measuring proteins associated with disease, or biomarkers, is an essential part of diagnostics and therapeutics in a wide range of therapeutic areas. Because aptamers can detect small differences between proteins, they are ideal for identifying small protein modifications associated with the surface proteins of diseased or cancerous cells. Using live cells, or cell-SELEX, it is possible to select aptamers that bind to a specific cell type. Adding negative selection with normal cells and known high-abundance cell-surface proteins, aptamers that bind to unique cell-surface proteins, or biomarkers, and are highly-selective for specific primary cell lines, can be developed. This method has been used to identify the transmembrane protein tyrosine kinase-7 (PTK7) as a biomarker for T-cell acute lymphoblastic leukemia and could be used to identify unknown or over-expressed proteins on the surface membrane of a wide range of cancer cells. Biomarker-specific aptamers are often applied in diagnostic assays, may function as a direct therapeutic, and have been complexed for targeting of diseased cells in drug delivery. Chang, Y. M. et al. Using Aptamers for Cancer Biomarker Discovery. Journal of Nucleic Acids. 2013. http://dx.doi.org/10.1155/2013/817350.
Cell-type-specific aptamers have been complexed with a range of therapeutic agents for targeted delivery, including siRNAs, miRNAs, therapeutic aptamers, chemotherapeutics, and toxins. Specific cell targeting has been shown to increase the local concentration of drug at the target site and improve overall drug efficacy. Cell targeting can also reduce the side effects associated with a number of therapeutic agents by reducing binding to normal cells (1). In a recent publication out of the Mashhad University of Medical Sciences, researchers developed an aptamer conjugate to specifically target murine colon cancer cells (C26) and breast cancer cells (MCF-7). Use of the aptamer complex increased uptake of the drug and toxicity in cancer cells compared with non-target CHO cells, caused pH-dependent drug release, and prohibited tumor growth in vivo. Use of aptamers for specific targeting of cancer cells can improve efficacy of drug compounds, reduce required dosage and decrease off-target effects (2). 1. Zhou, J. and Rossi, J. Aptamers as targeted therapeutics: current potential and challenges. Nature Reviews: Drug Discovery. 3 Nov 2016. Doi:101038/nrd.2016.199. 2. Yazdian-Robati, R. et al. Targeted delivery of Epirubican to cancer cells by polyvalent aptamer system in vitro and in vivo. Pharmaceutical Research. 19 Feb 2016. doi: 10.1007/s11095-016-1967-4.
The use of cell-SELEX to identify cell surface biomarkers for specific types of cancer cells and other disease cells yields new targets for the design of novel therapeutics and for therapeutic targeting. Aptamers selected for detection of unique cell types can be applied to diagnostic and screening applications, but can also be evaluated for direct therapeutic properties or for complexing with current therapeutic agents for more targeted drug delivery and reduction of off-target effects.
The expiration of exclusive intellectual property surrounding aptamer selection and improvements in aptamer technology and aptamer conjugates have paved the way for new aptamer applications in therapeutics and diagnostics. Nucleic acid aptamers with high affinity and selectivity can be raised against a wide range of targets, including targets that are toxic or non-immunogenic. Their small size, stability, cost-effective and highly controlled chemical synthesis, and low immunogenicity make aptamers attractive therapeutic agents. Ophthotech has two ongoing phase 2/3 clinical trials for aptamer drugs for age-related macular degeneration (1). On December 15, 2016 Noxxon signed an agreement with MSD to study NOX-A12, an aptamer against CXCL12 (SDF-1), in conjunction with Keytuda for the treatment of pancreatic and colorectal cancer. Aptamers that successfully target and enter NSCLC cells and induce apoptosis are in development as potential therapeutics (2). Advancements in aptamer technology and design are increasingly being applied to therapeutics, particularly in cases where conventional therapeutic techniques have fallen short. Base Pair is currently working with several clients to discover aptamers for specific therapeutic applications. 1. Zhou, J. and Rossi, J. Aptamers as targeted therapeutics: current potential and challenges. Nature Reviews: Drug Discovery. 3 Nov 2016. Doi:101038/nrd.2016.199. 2. Xu, Li, et al. Cellular internalization and cytotoxicity of aptamers selected from lung cancer cell. American Journal of Biomedical Sciences. 2013. 5(1):47-58. doi:10.5099/aj130100047.