Bioimaging, GSK, 1250 S. Collegeville Rd, Collegeville, PA, 19426, USA.
Certara UK Ltd, Sheffield, UK.
Eur J Nucl Med Mol Imaging. 2023 Feb;50(3):667-678. doi: 10.1007/s00259-022-06012-3. Epub 2022 Oct 28.
Sotrovimab (VIR-7831), a human IgG1κ monoclonal antibody (mAb), binds to a conserved epitope on the SARS-CoV-2 spike protein receptor binding domain (RBD). The Fc region of VIR-7831 contains an LS modification to promote neonatal Fc receptor (FcRn)-mediated recycling and extend its serum half-life. Here, we aimed to evaluate the impact of the LS modification on tissue biodistribution, by comparing VIR-7831 to its non-LS-modified equivalent, VIR-7831-WT, in cynomolgus monkeys.
Zr-based PET/CT imaging of VIR-7831 and VIR-7831-WT was performed up to 14 days post injection. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, with the focus on the respiratory tract, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics. Radiomics features were also extracted from the PET images and SUV values.
SUV uptake in the pulmonary bronchi for Zr-VIR-7831 was statistically higher than for Zr-VIR-7831-WT at days 6 (3.43 ± 0.55 and 2.59 ± 0.38, respectively) and 10 (2.66 ± 0.32 and 2.15 ± 0.18, respectively), while the reverse was observed in the liver at days 6 (5.14 ± 0.80 and 8.63 ± 0.89, respectively), 10 (4.52 ± 0.59 and 7.73 ± 0.66, respectively), and 14 (4.95 ± 0.65 and 7.94 ± 0.54, respectively). Though the calculated terminal half-life was 21.3 ± 3.0 days for VIR-7831 and 16.5 ± 1.1 days for VIR-7831-WT, no consistent differences were observed in the tissue:blood ratios between the antibodies except in the liver. While the lung:blood SUV uptake ratio for both mAbs was 0.25 on day 3, the PBPK model predicted the total lung tissue and the interstitial space to serum ratio to be 0.31 and 0.55, respectively. Radiomics analysis showed VIR-7831 had mean-centralized PET SUV distribution in the lung and liver, indicating more uniform uptake than VIR-7831-WT.
The half-life extended VIR-7831 remained in circulation longer than VIR-7831-WT, consistent with enhanced FcRn binding, while the tissue:blood concentration ratios in most tissues for both drugs remained statistically indistinguishable throughout the course of the experiment. In the bronchiolar region, a higher concentration of Zr-VIR-7831 was detected. The data also allow unparalleled insight into tissue distribution and elimination kinetics of mAbs that can guide future biologic drug discovery efforts, while the residualizing nature of the Zr label sheds light on the sites of antibody catabolism.
索特罗维单抗（VIR-7831）是一种人源 IgG1κ 单克隆抗体（mAb），可与 SARS-CoV-2 刺突蛋白受体结合域（RBD）上的保守表位结合。VIR-7831 的 Fc 区含有 LS 修饰，以促进新生 Fc 受体（FcRn）介导的循环和延长其血清半衰期。在这里，我们旨在通过比较 VIR-7831 与其非 LS 修饰的等效物 VIR-7831-WT，来评估 LS 修饰对组织分布的影响，在食蟹猴中进行。
使用基于 Zr 的 PET/CT 对 VIR-7831 和 VIR-7831-WT 进行成像，直至注射后 14 天。对所有主要器官进行绝对浓度分析以及组织与血液比值分析，重点是呼吸道，并使用基于生理学的药代动力学（PBPK）模型来评估组织分布动力学。还从 PET 图像中提取了放射组学特征和 SUV 值。
在第 6 天和第 10 天，Zr-VIR-7831 在肺支气管中的 SUV 摄取量明显高于 Zr-VIR-7831-WT（分别为 3.43±0.55 和 2.59±0.38，2.66±0.32 和 2.15±0.18），而在第 6 天、第 10 天和第 14 天，肝脏中的情况则相反（分别为 5.14±0.80 和 8.63±0.89，4.52±0.59 和 7.73±0.66，4.95±0.65 和 7.94±0.54）。虽然 VIR-7831 的计算终末半衰期为 21.3±3.0 天，而 VIR-7831-WT 的半衰期为 16.5±1.1 天，但除肝脏外，两种抗体的组织与血液比值没有一致的差异。尽管两种 mAb 在第 3 天的肺与血液 SUV 摄取比值均为 0.25，但 PBPK 模型预测总肺组织和间质空间与血清的比值分别为 0.31 和 0.55。放射组学分析表明，VIR-7831 在肺和肝脏中的 PET SUV 分布呈均值中心化，表明摄取比 VIR-7831-WT 更均匀。
半衰期延长的 VIR-7831 在循环中的半衰期长于 VIR-7831-WT，这与增强的 FcRn 结合一致，而两种药物在实验过程中大多数组织中的组织与血液浓度比值在统计学上仍无明显差异。在细支气管区域，检测到更高浓度的 Zr-VIR-7831。该数据还提供了对 mAb 组织分布和消除动力学的无与伦比的深入了解，可指导未来的生物药物发现工作，而 Zr 标记的残留特性揭示了抗体代谢的部位。
