Whole-Body Dynamic PET Imaging of Half-Life Extended Variable Domains of Heavy Chain-Only Antibodies: Beyond Blood Pharmacokinetics

Résumé fourni par la source

Nanobody molecules are single-domain antibodies derived from stable and fully functional heavy-chain-only (VHH) camelid antibodies. Due to their small size, approximately 15 kDa, their tissue distribution differs from that of conventional antibodies. This study investigates the whole-body pharmacokinetics (WBPK) and specific binding of half-life extended VHHs (HLE-VHHs) using dynamic whole-body immunoPET imaging in nonhuman primates. A HLE-VHH targeting the IL-6 receptor (CD126-VHH) and its nontargeting control (IRR-VHH) were evaluated in vivo after zirconium-89 radiolabeling. We compared microdoses (0.18 ± 0.11 mg/kg, n = 2) and/or pharmacological doses (coinjection, 3.19 ± 0.02 mg/kg, n = 2) of IRR-VHH, alongside microdoses of CD126-VHH (0.25 ± 0.14 mg/kg, n = 2). Initial dynamic whole-body PET scans (240 min) were followed by static PET scans on days 1, 7, and 14. We validated an image-derived input function against the arterial blood sampling method for kinetic modeling. [ 89 Zr]IRR-VHHs showed predominantly vascular distribution from day 0 to day 14, with comparable activity patterns and tissue distribution between microdose and pharmacological dose administrations. Early [ 89 Zr]CD126-VHH distribution mirrored the nonspecific IRR-VHH pattern, showing strong correlation ( R 2 = 0.87, slope = 1.1) in uptakes of organs, normalized to blood (standard uptake value ratio, SUVR) values at day 0. Interestingly, by days 7 and 14, [ 89 Zr]CD126-VHH exhibited higher uptake in bone marrow, spleen, liver, and kidneys, suggesting specific binding. The distribution of [ 89 Zr]IRR-VHH in these organs was assumed to reflect the nonspecific uptake of VHHs and was used to estimate the specific binding of [ 89 Zr]CD126-VHH. The specific binding of [ 89 Zr]CD126-VHH was similarly estimated using either the arterial input function or the image-derived input function (R 2 = 0.997, p < 0.0001). In plasma, the shorter elimination half-life of [ 89 Zr]CD126-VHH (2.0–1.8 days) compared to microdose [ 89 Zr]IRR-VHH (5.1–5.0 days) or pharmaco-dose [ 89 Zr]IRR-VHH (4.9–4.8 days) suggested target-mediated drug disposition. This study demonstrates the potential of immunoPET for evaluating the target-mediated drug disposition and WBPK of VHH molecules in vivo, providing valuable insights into VHH-based therapeutic strategies.

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