Kratochwil, Nicole A. Dueker, Stephen R. Muri, Dieter Senn, Claudia Yoon, HyeJin Yu, Byung-Yong Lee, Gwan-Ho Dong, Feng Otteneder, Michael B. 2024-01-19T21:32:47Z 2024-01-19T21:32:47Z 2021-09-04 2018-10-17 1932-6203 https://pubs.kist.re.kr/handle/201004/120783 New therapeutic biological entities such as bispecific antibodies targeting tissue or specific cell populations form an increasingly important part of the drug development portfolio. However, these biopharmaceutical agents bear the risk of extensive target-mediated drug disposition or atypical pharmacokinetic properties as compared to canonical antibodies. Pharmacokinetics and bio-distribution studies become therefore more and more important during lead optimization. Biologics present, however, greater analytical challenges than small molecule drugs due to the mass and selectivity limitation of mass spectrometry and ligand-binding assay, respectively. Radiocarbon (C-14) and its detection methods, such as the emerging C-14 cavity ring down spectroscopy (CRDS), thus can play an important role in the large molecule quantitation where a C-14-tag is covalently bound through a stable linker. CRDS has the advantage of a simplified sample preparation and introduction system as compared to accelerator mass spectrometry (AMS) and can be accommodated within an ordinary research laboratory. In this study, we report on the labeling of an anti-IL17 IgG 1 model antibody with C-14 propionate tag and its detection by CRDS using it as nanotracer (2.1 nCi or 77.7 Bq blended with the therapeutic dose) in a pharmacokinetics study in a pre-clinical species. We compare these data to data generated by AMS in parallel processed samples. The derived concentration time profiles for anti-IL17 by CRDS were in concordance with the ones derived by AMS and gamma-counting of an I-125-labeled anti-IL17 radiotracer and were well described by a 2-compartment population pharmacokinetic model. In addition, antibody tissue distribution coefficients for anti-IL17 were determined by CRDS, which proved to be a direct and sensitive measurement of the extravascular tissue concentration of the antibody when tissue perfusion was applied. Thus, this proof-of-concept study demonstrates that trace C-14-radiolabels and CRDS are an ultrasensitive approach in (pre)clinical pharmacokinetics and bio-distribution studies of new therapeutic entities. English PUBLIC LIBRARY SCIENCE ACCELERATOR MASS-SPECTROMETRY LASER SPECTROSCOPY RADIOCARBON ANTIBODIES PHARMACOKINETICS C-14 PARAMETERS DIOXIDE SAMPLES ADME Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies Article 10.1371/journal.pone.0205435 1 PLOS ONE, v.13, no.10 PLOS ONE 13 10 scie scopus 000447638200054 2-s2.0-85055071158 Multidisciplinary Sciences Science & Technology - Other Topics Article ACCELERATOR MASS-SPECTROMETRY LASER SPECTROSCOPY RADIOCARBON ANTIBODIES PHARMACOKINETICS C-14 PARAMETERS DIOXIDE SAMPLES ADME Cavity ring-down spectroscopy disposition large molecule accelerator mass spectrometry