Zhou Di, Kischel Roman, Stienen Sabine, Townsley Danielle, Sternjak Alexander, Lutteropp Michael, Bailis Julie, Friedrich Matthias, Rattel Benno, Mehta Khamir, Upreti Vijay V
Clinical Pharmacology Modeling & Simulation, Amgen Inc., South San Francisco, California, USA.
Amgen (Munich) GmbH, Munich, Germany.
Clin Pharmacol Ther. 2025 Jan;117(1):225-231. doi: 10.1002/cpt.3431. Epub 2024 Sep 16.
Bispecific T-cell engagers (Bi-TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best-in-class therapeutics for cancer. However, defining the dose and dosing regimen for the first-in-human (FIH) studies of Bi-TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub-therapeutic dosing. Leveraging our in-depth and broad clinical development experience across three generations of Bi-TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half-life extended (HLE) Bi-TCE for gastric cancer. This modified MABEL approach enabled a 10-fold higher starting dose that was deemed safe and well tolerated and saved at least two dose-escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi-TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi-TCEs.
双特异性T细胞衔接器（Bi-TCE）彻底改变了血液系统疾病和实体瘤适应症的治疗与管理方式，有机会成为癌症领域的同类最佳疗法。然而，确定Bi-TCE首次人体（FIH）研究的剂量和给药方案可能具有挑战性，因为高起始剂量可能使受试者面临严重毒性，而基于传统最小预期生物学效应水平（MABEL）方法的低起始剂量可能导致漫长的剂量爬坡，使重症患者接受亚治疗剂量。利用我们在三代Bi-TCE针对液体和实体瘤适应症的深入广泛临床开发经验，我们开发了一种创新的改良MABEL方法用于起始剂量选择，该方法整合了基于靶标生物学、适应症、毒理学、体外、体内药理学评估以及转化药代动力学/药效学（PK/PD）建模的知识，以及预期的安全性概况。与通常使用高效应细胞与靶细胞（E:T）比例的传统MABEL方法相比，我们的创新方法采用了优化的E:T细胞比例，能更好地反映肿瘤微环境。这种改良的MABEL方法成功应用于一种用于胃癌的半衰期延长（HLE）Bi-TCE的FIH剂量选择。这种改良的MABEL方法使起始剂量提高了10倍，且被认为安全且耐受性良好，并在达到预计的有效剂量之前至少节省了两个剂量爬坡队列。该方法已成功获得全球监管机构的认可，可应用于血液系统疾病和实体瘤适应症的Bi-TCE，以加速Bi-TCE的临床开发。
