"Using Aro’s proprietary Centyrin technology, we have demonstrated potent functional delivery of siRNA oligonucleotides into skeletal and heart muscle while sparing knockdown in other tissues. Centyrins are ~10kDa protein ligands that combine the affinity and specificity properties of antibodies with significantly improved biophysical properties. Centyrins’ small size, lack of immunogenicity, scalable, cost-efficient manufacturing in E. Coli, and site-specific conjugation make them ideally suited for targeted delivery of oligonucleotides to extra-hepatic tissues. Thus, Centyrins represent a potential solution to the well-recognized challenge of delivery of oligonucleotide medicines to tissues outside of the liver.
Using large libraries of Centyrin variants, we have identified a panel of Centyrin leads that bind to human transferrin receptor 1 (CD71, TfR1) and are not competitive with transferrin. Centyrin leads were evaluated for immunogenicity and were found to be devoid of T cell epitopes. Cysteine residues were introduced at specific amino acid sites in the Centyrin framework which enabled homogeneous, site-specific conjugation to siRNAs and ASOs. In animal models, Centyrins were shown to efficiently target conjugated siRNAs or ASOs to muscle, leading to robust knockdown of target genes in skeletal muscle and heart, with excellent tolerability profiles.
Given that Centyrins are of a similar size as the oligonucleotide cargo, Centyrin oligonucleotide drug conjugate doses are significantly lower than antibody or antibody fragment-based conjugates, reducing the potential for acute infusion reactions and immunogenicity. As a result of these unique properties, Centyrins hold promise as a new class of oligonucleotide conjugate therapies, with superior developability properties and potential for best-in-class efficacy and safety.