BI 836880 是一种人源化双特异性纳米抗体®，可结合并阻断血管内皮生长因子 (VEGF) 和血管生成素-2 (Ang-2)。这里提出了一种全面的生物标志物和建模方法，支持 BI 836880 的剂量发现。两项 I 期剂量递增研究（1336.1 [NCT02674152]、1336.6 [NCT02689505]）在确诊为局部晚期或转移性实体瘤、难治性的成人中评估了 BI 836880接受标准治疗或标准治疗不能可靠有效。研究了两种给药方案，即 3 周 (q3w) 或每周一次 (qw)，起始剂量为 40 mg。在综合生物标志物方法中，分析可溶性药效标志物（游离和总血浆 VEGF-A 和 Ang-2）以及循环血管生成因子（可溶性 VEGF3、可溶性 Tie2 和胎盘生长因子等），以评估靶点参与情况每 3 周一次剂量的外周血。使用有限的 I 期数据集构建了基于群体的药代动力学/药效学 (PopPK/PD) 模型，以支持通过模拟发现剂量。为了证明药物在肿瘤中的活性，应用了动态对比增强磁共振成像（DCE-MRI）。DCE-MRI 扫描支持肿瘤中的靶标参与。游离 VEGF-A 在所有剂量下均被耗尽，而游离 Ang-2 呈剂量依赖性下降，大多数患者从 360 mg q3w 开始就达到了耗尽。虽然总 VEGF-A 水平以剂量依赖性方式增加，在 360 mg q3w 时达到饱和，但总 Ang-2 水平有所增加，但并未达到稳定水平。血管生成生物标志物显示出剂量≥≥360 mg q3w 的变化。 PopPK/PD 模型显示，剂量 ≥ 360 mg q3w 会导致大多数患者在稳态时对游离 Ang-2 产生 >90% 的抑制。通过将剂量增加至 ≥ 500 mg q3w， > 90%的患者有望达到这一水平。多个靶标参与标记物的综合分析支持BI 836880 720 mg q3w作为生物学相关的单药治疗剂量方案。NCT02674152和NCT02689505。© 2024 . 作者。

BI 836880 is a humanized bispecific nanobody® that binds to and blocks vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2). A comprehensive biomarker and modeling approach is presented here that supported dose finding for BI 836880.Two Phase I dose-escalation studies (1336.1 [NCT02674152], 1336.6 [NCT02689505]) assessed BI 836880 in adults with confirmed locally advanced or metastatic solid tumors, refractory to standard therapy or for which standard therapy was not reliably effective. Two dosing schedules were investigated, 3 weeks (q3w) or once weekly (qw), starting at a dose of 40 mg. In a comprehensive biomarker approach, soluble pharmacodynamic markers (free and total plasma VEGF-A and Ang-2), as well as circulating angiogenic factors (soluble VEGF3, soluble Tie2 and placenta growth factor, amongst others) were analyzed to assess target engagement in peripheral blood for q3w doses. A Population based pharmacokinetics/pharmacodynamics (PopPK/PD) model was built using the limited Phase I dataset to support dose finding by simulations. In order to demonstrate drug activity in the tumor, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was applied.DCE-MRI scans supported target engagement in the tumor. Free VEGF-A was depleted at all doses, whereas free Ang-2 decreased dose-dependently, reaching depletion in most patients from 360 mg q3w onwards. While total VEGF-A levels increased in a dose-dependent manner, reaching saturation at 360 mg q3w, total Ang-2 levels increased, but did not plateau. Angiogenic biomarkers showed changes from doses ≥ 360 mg q3w. PopPK/PD modeling showed that doses ≥ 360 mg q3w led to > 90% inhibition of free Ang-2 at steady-state in most patients. By increasing the dose to ≥ 500 mg q3w, > 90% of patients are expected to achieve this level.The comprehensive analyses of multiple target engagement markers support BI 836880 720 mg q3w as a biologically relevant monotherapy dose schedule.NCT02674152 and NCT02689505.© 2024. The Author(s).