In-Vivo Degradation of DNA-Based Therapeutic BC 007 in Humans

Background and ObjectivesSince there is no clear evidence in the literature to show how non-modified single-stranded DNA (ssDNA) drugs are metabolized in humans, we assessed the metabolism of BC 007, an ssDNA therapeutic, under development as a neutralizer of autoantibodies against G-protein-coupled receptors. In-vitro, investigating its stability in monkey plasma and serum, a successive 3-exonuclease degradation resulting in several n-x degradation products has been previously reported. Here, we investigated the metabolism of BC 007 in humans after intravenous application to autoantibody-positive healthy subjects, in line with Phase I safety testing.Methods(1)H-NMR was applied for n-x degradation product search and beta-aminoisobutyric acid (bAIBA) measurement in urine; ultra-performance liquid chromatography-mass spectrometry was also used for the latter. Colorimetric assays were used for quantification of uric acid in serum and urine.ResultsFast degradation prohibited the detection of the intermediate n-x degradation products in urine using H-1-NMR. Instead, NMR revealed a further downstream degradation product, bAIBA, which was also detected in serum shortly after initial application. The purine degradation product, uric acid, confirmed this finding of fast metabolism.Conclusion Fast and full degradation of BC 007, shown by nucleic bases degradation products, is one of the first reports about the fate of a ssDNA product in humans.