Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
NPJ Syst Biol Appl. 2020 Aug 28;6(1):28. doi: 10.1038/s41540-020-00145-7.
Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of B- and T-lymphocytes in circulation, lymphoid tissues, and tumor. The model was developed and validated using mosunetuzumab nonclinical and blinatumomab clinical data. Simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response. These results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses.
莫努匹韦单抗是一种 T 细胞依赖性双特异性抗体，能同时结合 CD3 和 CD20，从而驱动 T 细胞介导的 B 细胞杀伤，目前正在非霍奇金淋巴瘤中进行测试。然而，针对 T 细胞的靶向治疗会引起强烈的免疫刺激，从而导致细胞因子释放综合征，可能会限制剂量和应用。为了了解安全性和疗效背后的机制，并探索安全缓解策略，我们开发了一种新型的 T 细胞双特异性药物（莫努匹韦单抗和blinatumomab）的免疫和抗肿瘤反应机制模型，包括循环、淋巴组织和肿瘤中的 B 细胞和 T 细胞的动力学。该模型使用莫努匹韦单抗的非临床数据和blinatumomab 的临床数据进行了开发和验证。模拟结果阐明了导致观察到的细胞和细胞因子（IL6）动力学的机制，并预测初始分步剂量给药不会影响肿瘤反应，但可限制全身 T 细胞激活和细胞因子释放。这些结果支持了在正在进行的 I 期临床试验中改变莫努匹韦单抗的分步治疗方案，从而能够更安全地给予更高剂量。
