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

Abstract

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.

A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects

“…In all subjects of Cohorts 4 and 5 (1350 and 1900 mg), an increase in uric acid was seen, beginning 50 min after the start of the infusion, with peak values at 120 and 110 min after the start of the infusion, respectively, with only slight elevation left on Day 2 and complete return to baseline on Day 8. This increase was within the normal physiologic range [23].…”

“…With respect to metabolism, the proportion of 7% of 3′-exonuclease cleaved compound is low, especially since Shaw et al published an effective 3′-exonuclease decay in monkey plasma and serum in 1995 [21]. It was, therefore, also already looked for further down breakdown products, identifying the increase of nucleobase decay products immediately after the start of the infusion, which was described in detail by Davideit et al [23]. This fast and full degradation down to nucleic base degradation products in humans was an astonishing fact and one of the first reports about the fate of DNA-drugs in humans.…”

Signaling metabolite β-aminoisobutyric acid as a metabolic regulator, biomarker, and potential exercise pill

“…Kittel et al. ( 86 ) detected three-fold higher plasma BAIBA concentrations in a small number of subjects with AGXT2 gene deficit; however, none of the studies reported any adverse effect of increased endogenous BAIBA, suggesting that endogenous and exogenous factors resulting in high plasma BAIBA levels do not have any pathological effect ( 87 ). Notably, in pathological situations with substantial DNA degradation, such as malignancy ( 84 , 88 ), radiation ( 89 ), and short-term starvation ( 90 ), the levels of BAIBA in urine are elevated.…”

“…Although BAIBA can be detected in both blood and urine, the time course in the two matrices may not be the same. After an intervention with the DNA-based drug BC007, plasma BAIBA concentrations were found to increase after 3 min, reached a maximum after 60 min, and declined to baseline levels ( 87 ). The same intervention led to a rise in urinary BAIBA levels within a maximum of 2−4 h and a decline to pre-intervention levels over 8–12 h. BAIBA was considered to be metabolized rapidly in plasma, with urine representing a better matrix for testing, since sampling is non-invasive and the time profile is more favorable for testing.…”

β 1 -Adrenoreceptor Autoantibodies in Heart Failure

“…The 2 products may be useful in tracking the metabolism of the drug. 81 According to the sponsor, BC007 is currently under investigation for persistence of β 1 -AR autoantibody removal in autoantibody-positive HF patients in phase IIa of clinical testing.…”