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

BACKGROUND AND OBJECTIVES: Since 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. RESULTS: Fast degradation prohibited the detection of the intermediate n–x degradation products in urine using (1)H-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.