Expanding the concept of chemically programmable antibodies to RNA-aptamers: a novel class of chemically programmed biotherapeutics

• Published in: Angewandte Chemie International Edition Vol. 49; no. 34; pp. 5934 - 5937
• Main Authors: Wuellner, Ulrich, Gavrilyuk, Julia I., Barbas, Carlos F.
• Format: Journal Article
• Language: English
• Published: 09.08.2010
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201001736

Chemically programmed antibodies represent a new class of biologic drugs that acquire their specificity through chemistry rather than through biology. To date, this approach has used small molecules and peptides to direct targeting and to extend the pharmacokinetics and otherwise enhance the biological function of the small molecule or peptide through Fc-based mechanisms of the antibody. However, other classes of therapeutically active molecules, such as aptamers, should benefit from antibody conjugation and the chemically programmed antibody approach. Aptamers are structured nucleic acid ligands often selected using the ‘selective evolution of ligands by exponential enrichment’ (SELEX) procedure. Although aptamers are a promising class of therapeutics because of their excellent binding and inhibitory properties, only a single VEGF-targeting aptamer is an approved drug. For in vivo applications, aptamers suffer from low chemical stability (these molecules are readily degraded by nucleases in serum) and poor pharmacokinetic properties (circulatory half lives are on the order of several minutes). Nuclease resistance can be enhanced significantly by incorporating 2’ ribose modified nucleobases; 2’-O-methyl modified oligonucleotides have acceptable serum stabilities. Other oligonucleotide modifications are also being explored to solve this difficult problem. Here, we demonstrate for the first time site-specific conjugation of an aptamer to the aldolase antibody 38C2 to produce aptamer programmed cpAbs. Conjugation of the VEGF-targeting aptamer ARC245 to the well-characterized chemically programmable antibody 38C2 resulted in a biologically active aptamer-antibody conjugate that had significantly increased functional affinity and circulatory half-life as compared to the free aptamer. The aptamer-cpAb strategy developed here should be general and readily transferable to other aptamers. Aptamer-based cpAbs of the type developed here represent a promising new class of aptamer immunotherapeutics that combine the favourable characteristics of aptamers with those of antibodies.