Biotherapeutics Discovery, Research & Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Rd./P.O. Box 368, Ridgefield, Connecticut, 06877-0368, USA.
AAPS PharmSciTech. 2023 Nov 21;24(8):236. doi: 10.1208/s12249-023-02689-3.
Antibody-based therapeutics have recently gained keen attention for the treatment of pulmonary indications. However, systemically administered antibody exposure in the lungs needs to be better understood and remains a topic of interest. In this study, we evaluated the exposure of two different uPAR (urokinase-type plasminogen activator receptor) targeting full-length monoclonal IgGs in plasma and lung epithelial lining fluid (ELF) of mice after IP and IV administration. Antibody AK17 exhibited linear pharmacokinetics (PK) in plasma and ELF at 3 and 30 mg/kg single IV dose. The average plasma and ELF half-lives for AK17 and AK21 ranged between ~321-411 h and ~230-345 h, respectively, indicating sustained systemic and lung exposure of antibodies. The average ELF to the plasma concentration ratio of antibodies was ~0.01 and ~0.03 with IP and IV dosing, respectively, over 2 weeks post single dose. We simultaneously characterized plasma and ELF PK of antibody in mice by developing a minimal lung PBPK model for antibody. This model reasonably captured the plasma and ELF PK data while estimating three parameters. The model accounts for the convective transport of antibody into the tissues via blood and lymph flow. FcRn-mediated transcytosis was incorporated into the model for antibody distribution across the lung epithelial barrier. This model serves as a platform to predict the pulmonary PK of systemically administered antibodies and to support optimal dose selection for desired exposure in the lungs as the site of action.
抗体类药物最近在肺部疾病的治疗方面受到了广泛关注。然而，肺部系统给药后的抗体暴露情况仍需要深入研究，这也是一个备受关注的课题。在这项研究中，我们评估了两种不同的 uPAR（尿激酶型纤溶酶原激活物受体）靶向全长单克隆 IgG 在 IP 和 IV 给药后小鼠血浆和肺上皮衬液（ELF）中的暴露情况。抗体 AK17 在 3 和 30 mg/kg 单剂量 IV 给药时，在血浆和 ELF 中表现出线性药代动力学（PK）特征。AK17 和 AK21 的平均血浆和 ELF 半衰期分别在 321-411 h 和 230-345 h 之间，表明抗体具有持续的全身和肺部暴露。单次给药后 2 周内，通过 IP 和 IV 给药，抗体的平均 ELF 与血浆浓度比分别约为 0.01 和 0.03。我们通过开发最小化的肺 PBPK 模型同时对抗体的血浆和 ELF PK 进行了特征描述。该模型在估计三个参数的同时，合理地捕捉了血浆和 ELF PK 数据。该模型考虑了抗体通过血流和淋巴流向组织的对流转运。将 FcRn 介导的胞吞作用纳入模型，以描述抗体在肺上皮屏障中的分布。该模型可用于预测系统给药抗体的肺部 PK，并支持最佳剂量选择，以实现所需的肺部暴露作为作用部位。
