CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Nonclinical Pharmacokinetics, Pharmacodynamics, and Translational Model of RO7297089, A Novel Anti-BCMA/CD16A Bispecific Tetravalent Antibody for the Treatment of Multiple Myeloma.
Nonclinical Pharmacokinetics, Pharmacodynamics, and Translational Model of RO7297089, A Novel Anti-BCMA/CD16A Bispecific Tetravalent Antibody for the Treatment of Multiple Myeloma.
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RO7297089是一种靶向B细胞成熟抗原（BCMA）和CD16A的双特异性四价抗体，正在开发用于治疗多发性骨髓瘤（MM）。
本研究评估其非临床药代动力学（PK）、药效学（PD），以及给药后可溶性BCMA（sBCMA）和可溶性CD16（sCD16）的变化，以支持后续临床试验。研究测定食蟹猴体内游离和总RO7297089浓度。其全身浓度-时间曲线呈双相变化，类似典型人免疫球蛋白G1抗体。RO7297089靶点结合使全身总sBCMA水平显著升高（约100倍），而总sCD16水平仅轻度升高（约2倍）。为描述非临床PK/PD数据之间的关系，研究人员建立了靶点介导药物处置（TMDD）模型，纳入膜型BCMA（mBCMA）、sBCMA、膜型CD16（mCD16）和sCD16的全身靶点结合情况。随后依据文献及新获得数据（如基线sCD16A水平）转换相关PK参数和靶点水平，使用该模型模拟MM患者的RO7297089 PK/PD关系。模型提示，与健康食蟹猴相比，MM患者mBCMA和sBCMA表达显著升高，因此TMDD对RO7297089暴露量的影响可能更大。模型模拟结果还表明，治疗初期应比常规每月给药更频繁，以确保持续结合靶点。
本研究展示了转化研究策略：收集相关非临床数据、建立TMDD模型，并通过模型模拟为临床剂量方案提供依据。
RO7297089, an anti-B-cell maturation antigen (BCMA)/CD16A bispecific tetravalent antibody, is being developed as a multiple myeloma (MM) therapeutic.
This study characterized nonclinical pharmacokinetics (PK), pharmacodynamics (PD), soluble BCMA (sBCMA), and soluble CD16 (sCD16) changes following administration of RO7297089 to support clinical trials. Unbound and total RO7297089 concentrations were measured in cynomolgus monkeys. RO7297089 exhibited a bi-phasic systemic concentration-time profile, similar to a typical human immunoglobulin 1 antibody.
Target engagement by RO7297089 led to a robust increase (~100-fold) in total systemic sBCMA levels and relatively mild increase (~2-fold) in total sCD16 levels. To describe the relationship of nonclinical PK/PD data, we developed a target-mediated drug disposition (TMDD) model that includes the systemic target engagement of membrane BCMA (mBCMA), sBCMA, membrane CD16 (mCD16), and sCD16.
We then used this model to simulate the PK/PD relationship of RO7297089 in MM patients by translating relevant PK parameters and target levels, based on the literature and newly generated data such as baseline sCD16A levels.
Our model suggested that the impact of TMDD on RO7297089 exposure may be more significant in MM patients due to significantly higher expression levels of both mBCMA and sBCMA compared to healthy cynomolgus monkeys. Based on model simulations, we propose more frequent dosing of RO7297089 compared to regular monthly frequency in the clinic at the beginning of treatment to ensure sustained target engagement.
This study demonstrates a translational research strategy for collecting relevant nonclinical data, establishing a TMDD model, and using simulations from this model to inform clinical dose regimens.
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