1. Nanotracing and cavity-ring down spectroscopy: A new ultrasensitive approach in large molecule drug disposition studies
- Author
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Nicole A. Kratochwil, Michael B. Otteneder, Gwan-Ho Lee, Dieter Muri, Claudia Senn, Hyejin Yoon, Stephen R. Dueker, Byung-Yong Yu, and Feng Dong
- Subjects
Physiology ,lcsh:Medicine ,030226 pharmacology & pharmacy ,01 natural sciences ,Mass Spectrometry ,Iodine Radioisotopes ,0302 clinical medicine ,Immune Physiology ,Medicine and Health Sciences ,Tissue Distribution ,Carbon Radioisotopes ,Enzyme-Linked Immunoassays ,lcsh:Science ,education.field_of_study ,Multidisciplinary ,Chemistry ,Interleukin-17 ,Antibodies, Monoclonal ,Small molecule ,Body Fluids ,Biopharmaceutical ,Blood ,Drug development ,Optical Equipment ,Engineering and Technology ,Anatomy ,Research Article ,Population ,Muscle Tissue ,Equipment ,Mass spectrometry ,Research and Analysis Methods ,Blood Plasma ,03 medical and health sciences ,Therapeutic index ,Pharmacokinetics ,Humans ,Plasma Volume ,education ,Immunoassays ,Pharmacology ,Chromatography ,Spectrum Analysis ,Lasers ,010401 analytical chemistry ,lcsh:R ,Biology and Life Sciences ,Kidneys ,Renal System ,0104 chemical sciences ,Biological Tissue ,Immunologic Techniques ,lcsh:Q ,Linker ,Spleen - Abstract
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 (14C) and its detection methods, such as the emerging 14C cavity ring down spectroscopy (CRDS), thus can play an important role in the large molecule quantitation where a 14C-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 IgG1 model antibody with 14C 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 preclinical 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 γ-counting of an 125I-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 14C-radiolabels and CRDS are an ultrasensitive approach in (pre)clinical pharmacokinetics and bio-distribution studies of new therapeutic entities.
- Published
- 2018