Li Yuezhe, Wilkins A Katharina, Davis Jimena, Knab Timothy, Toukam Marie, Boni Joseph P, Kirouac Daniel C
Metrum Research Group, 68 Harrison Ave, Boston, MA, USA.
ADC Therapeutics America, New Providence, NJ, USA.
NPJ Syst Biol Appl. 2025 Jun 11;11(1):63. doi: 10.1038/s41540-025-00544-8.
Antibody-drug conjugates (ADCs) and T-cell-dependent bispecific antibodies (TDBs) show single-agent efficacy in relapsed/refractory (R/R) lymphomas. While coadministering therapeutics with orthogonal mechanisms of action may safely enhance efficacy, testing every potential combination regimen is infeasible in the clinic. An integrated quantitative systems pharmacology model of a CD19-targeted ADC and CD3/CD20-targeted TDBs was developed to predict combination regimen efficacy in R/R diffuse large B-cell lymphoma (DLBCL). Clinically validated models of the ADC loncastuximab tesirine and TDB mosunetuzumab were combined and extended to additional TDBs (glofitamab and epcoritamab). Virtual DLBCL populations were calibrated using monotherapy response data, and tumor volume dynamics simulated under alternate combination dosing regimens and patient scenarios. Additive antitumor effects were predicted from the fourth cycle onward, with combination efficacy insensitive to loncastuximab tesirine dose reductions or patient lymphopenias. Results of the LOTIS-7 study (NCT04970901) will soon be available to assess these predictions.
抗体药物偶联物（ADC）和T细胞依赖性双特异性抗体（TDB）在复发/难治性（R/R）淋巴瘤中显示出单药疗效。虽然将具有正交作用机制的治疗药物联合使用可能会安全地提高疗效，但在临床上测试每一种潜在的联合治疗方案是不可行的。因此，建立了一个针对CD19的ADC和针对CD3/CD20的TDB的综合定量系统药理学模型，以预测R/R弥漫性大B细胞淋巴瘤（DLBCL）的联合治疗方案疗效。将ADC loncastuximab tesirine和TDB mosunetuzumab的临床验证模型进行合并，并扩展到其他TDB（glofitamab和epcoritamab）。使用单药治疗反应数据对虚拟DLBCL群体进行校准，并在不同的联合给药方案和患者情况下模拟肿瘤体积动态。从第四个周期开始预测联合用药的抗肿瘤效果，联合疗效对loncastuximab tesirine剂量降低或患者淋巴细胞减少不敏感。LOTIS-7研究（NCT04970901）的结果将很快公布，以评估这些预测。
