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.

Mosunetuzumab 是一种 T 细胞依赖性双特异性抗体，可结合 CD3 和 CD20 以驱动 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，用 T 细胞定向疗法进行有效的免疫刺激会带来细胞因子释放综合征的风险，可能会限制剂量和效用。为了了解安全性和有效性背后的机制并探索安全缓解策略，我们开发了一种新的免疫和抗肿瘤反应机制模型，对 T 细胞双特异性药物（mosunetuzumab 和 blinatumomab），包括 B 和 T 淋巴细胞在循环中的动态，淋巴组织, 肿瘤. 该模型是使用 mosunetuzumab 非临床和 blinatumomab 临床数据开发和验证的。模拟描绘了有助于观察到的细胞和细胞因子 (IL6) 动力学的机制，并预测初始分步给药会限制全身性 T 细胞活化和细胞因子释放，而不会影响肿瘤反应。这些结果支持在正在进行的 I 期临床试验中改变 mosunetuzumab 的分阶段治疗方案，从而能够更安全地施用更高剂量。