Bajaj Gaurav, Shchelokov Dmitry, Demin Oleg, Adams Homer C, Feng Yan, Gibiansky Leonid, van der Lee Saskia, Johri Anandhi, Belete Merzu, Muik Alexander, Panorchan Porntula, Türeci Özlem, Sahin Uğur, Ahmadi Tahamtan, Gupta Manish, Demin Oleg, Thalhauser Craig
Genmab, Plainsboro, New Jersey, USA.
InSysBio CY, Limassol, Cyprus.
Clin Pharmacol Ther. 2025 Aug;118(2):418-427. doi: 10.1002/cpt.3677. Epub 2025 May 10.
Optimizing target engagement for bispecific antibodies (bsAbs) is challenging, as bsAbs bind to two different targets in vivo to form a trimolecular complex (trimer), and likely display a bell-shaped concentration-response curve. bsAbs trimer formation is expected to be related to efficacy and safety, and determining the dose level at which it is achieved may support dose selection; however, trimer levels currently cannot be quantified in vivo. GEN1042 (DuoBody®-CD40x4-1BB)-a novel, agonistic bsAb-combines targeting and conditional activation of co-stimulatory molecules CD40 and 4-1BB on immune cells, resulting in enhanced priming and reactivation of tumor-specific immunity. We describe data and models that supported GEN1042 dose selection for expansion, including a minimal physiologically based pharmacokinetic and receptor occupancy (mPBPK/RO) model that can predict levels of GEN1042 trimers crosslinked to CD40 and 4-1BB in tumors and lymph nodes to guide dose selection. The model leverages PK data, physiologic parameters, and in vitro data from the literature for parameterization of GEN1042 kinetics and distribution, its interaction with target receptors CD40 and 4-1BB, and their expression on the surface of various cell types. Trimer level outcomes were further assessed with clinical data for dose selection. An initial expansion dose of GEN1042 100 mg every 3 weeks was chosen based on available clinical safety/tolerability, efficacy, PK/pharmacodynamics data, mPBPK/RO, and exposure-response analysis. This dose level is currently being evaluated in combination with pembrolizumab, with or without chemotherapy, in the expansion phase of the GEN1042 phase 1/2 trial (NCT04083599); other alternative doses are currently being explored.
优化双特异性抗体（bsAb）的靶点结合具有挑战性，因为bsAb在体内与两个不同靶点结合形成三聚体复合物（三聚体），并且可能呈现钟形浓度-反应曲线。bsAb三聚体的形成预计与疗效和安全性相关，确定实现该状态的剂量水平可能有助于剂量选择；然而，目前无法在体内对三聚体水平进行量化。GEN1042（DuoBody®-CD40x4-1BB）是一种新型的激动型bsAb，它结合并条件性激活免疫细胞上的共刺激分子CD40和4-1BB，从而增强肿瘤特异性免疫的启动和再激活。我们描述了支持GEN1042扩展剂量选择的数据和模型，包括一个基于最小生理学的药代动力学和受体占有率（mPBPK/RO）模型，该模型可以预测肿瘤和淋巴结中与CD40和4-1BB交联的GEN1042三聚体水平，以指导剂量选择。该模型利用PK数据、生理学参数和文献中的体外数据对GEN1042的动力学和分布、其与靶点受体CD40和4-1BB的相互作用以及它们在各种细胞类型表面的表达进行参数化。通过临床数据进一步评估三聚体水平结果以进行剂量选择。根据现有的临床安全性/耐受性、疗效、PK/药效学数据、mPBPK/RO和暴露-反应分析，选择了GEN1042每3周100mg的初始扩展剂量。目前正在GEN1042 1/2期试验（NCT04083599）的扩展阶段评估该剂量水平与帕博利珠单抗联合使用（有或无化疗）的情况；目前正在探索其他替代剂量。
