Session 5: Molecular biology – II

Monoclonal antibodies were developed three decades ago. Today they are used in a wide range of applications, including the targeted therapy of human neoplasia. There are now eight monoclonal antibody based therapeutics approved for the treatment of cancer, and, monoclonals represent one of the fastest growing categories of new drug approvals in oncology. A new class of molecules, which like monoclonal antibodies, display both specificity and high affinity for their target, is now emerging. These drugs are Aptamers, agents that, despite their functional parallels with antibodies, are nucleic acid molecules rather than glycoproteins. These aptamers have a number of properties that make them attractive as a new class of therapeutic molecules. Aptamers were first discovered by virologists studying HIV and adenovirus. They found several small, structured RNAs that bound to viral proteins and either modulated their activity, which was vital to replication, or inhibited the function of proteins involved in cellular antiviral responses. Over the past decade, large libraries of RNA and DNA aptamers have been generated, using the systematic evolution of ligands by exponential enrichment (SELEX) process, developed by Tuerk & Gold. The targets for these aptamers vary widely, and include dyes, viral proteins, NF-kappa B, Tenascin-C, by probing antigens presented by a monolayer of glioblastoma derived cells, hepatitis C virus proteases, TNFalpha, protein kinase C, thrombin, factor VIIa, VEGF, PDGF-Beta, PSMA and nucleolin. Two aptamers are in clinical trials, and one, an anti-VEGF aptamer, is approved for the treatment of macular degeneration. One of the ongoing clinical trials, utilises a G-rich DNA aptamer, that binds specifically to nucleolin, a protein found in the nucleus and cytoplasm of normal cells, but also expressed on the cell membrane of both tumour cells and tumour vascular, endothelial cells. This DNA aptamer, previously known as AGRO-100, and now AS1411, entered clinical trials at the Brown Cancer Centre, Louisville, Kentucky, and in a phase I clinical trial has been shown to induce both stable disease and partial responses in patients with a variety of tumour types. The properties, in-vitro, in-vivo and clinical, of this aptamer to nucleolin will be discussed.