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.
Highlights
Radioisotopic labeling, especially with radiocarbon, is an excellent tool in pharmaceutical science and has widespread utility in absorption, distribution, metabolism and elimination (ADME) studies in preclinical species and man [1]
We demonstrate the use of a 14C-nanotracer and cavity ring down spectroscopy (CRDS) in a pharmacokinetic study of a therapeutic antibody
The 14C CRDS spectrometry gave equivalent pharmacokinetic results as compared to accelerator mass spectrometry (AMS), the correlation being strong in plasma, a homogeneous matrix
Summary
Radioisotopic labeling, especially with radiocarbon, is an excellent tool in pharmaceutical science and has widespread utility in absorption, distribution, metabolism and elimination (ADME) studies in preclinical species and man [1]. The familiar, analytical tools are 11C positron emission tomography, scintillation counting, and accelerator mass spectrometry (AMS) for carbon-14C radiolabeled compounds [5]. AMS provides high sensitivity quantitation of the 14C contents in a sample containing any 14C-labeled species, often with limited need for internal standards or calibration plots as quantitation is based upon an intrinsic part of the molecule, i.e. the 14C label. AMS is arguably one of the most sensitive (and precise) analytical techniques [6].This form of ion beam physics is still largely similar in operation to the form first described in the late 1970’s with significant improvements in overall size (footprint) [7], and sample processing and introduction systems [8]. Despite the value AMS can bring to clinical (and less often non-clinical) trials, it remains a niche tool that is complex, expensive, and requires skilled facility personnel
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