Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland.
Department of Pharmacy, Uppsala University, Uppsala, Sweden.
AAPS J. 2022 Oct 7;24(6):106. doi: 10.1208/s12248-022-00755-5.
TYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-L1 combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also induces a faster rate of tumor regrowth. Combination with anti-PD-L1 extended the time to tumor regrowth by 25% while also decreasing the tumor regrowth rate by 69% compared to the same dose of TYRP1-TCB alone. The model translation to humans predicts that if patients' tumors were scanned every 6 weeks, only 46% of the monotherapy responders would be detected even at a TYRP1-TCB dose resulting in exposures above the EC. However, combination of TYRP1-TCB and anti-PD-L1 in the clinic is predicted to more than double the overall response rate (ORR), duration of response (DoR) and progression-free survival (PFS) compared to TYRP1-TCB monotherapy. As a result, it is highly recommended to consider development of CD3-TCBs as part of a combination therapy from the outset, without the need to escalate the CD3-TCB up to the Maximum Tolerated Dose (MTD) in monotherapy and without gating the combination only on RECIST-derived efficacy metrics.
TYRP1-TCB 是一种用于治疗晚期黑色素瘤的 CD3 T 细胞双特异性（CD3-TCB）抗体。使用 TYRP1-TCB 单药治疗或 TYRP1-TCB 联合抗 PD-L1 联合治疗的小鼠异种移植数据开发了肿瘤生长抑制（TGI）模型。该模型被转化为人类，以提供更精细的临床策略。从异种移植小鼠数据中，我们估计 TYRP1-TCB 的 EC 为 0.345mg/L，接近使用相同肿瘤细胞系在体外观察到的结果。该模型表明，虽然增加 TYRP1-TCB 的单药剂量会延迟肿瘤复发的时间并促进更高的肿瘤细胞杀伤，但也会导致肿瘤更快地复发。与 TYRP1-TCB 单药治疗相比，联合使用抗 PD-L1 将肿瘤复发时间延长了 25%，同时也将肿瘤复发率降低了 69%。该模型的人体翻译预测，如果每隔 6 周对患者的肿瘤进行扫描，即使在导致 EC 以上暴露的 TYRP1-TCB 剂量下，也只有 46%的单药应答者会被检测到。然而，与 TYRP1-TCB 单药治疗相比，TYRP1-TCB 联合抗 PD-L1 在临床上预计将使总缓解率（ORR）、缓解持续时间（DoR）和无进展生存期（PFS）翻倍以上。因此，强烈建议从一开始就将 CD3-TCB 作为联合治疗的一部分进行开发，而无需将 CD3-TCB 单药剂量增加到最大耐受剂量（MTD），并且无需仅根据 RECIST 衍生的疗效指标来限制联合治疗。
