Tarlatamab

Tarlatamab (AMG-757) is a bispecific T-cell engager (BiTE) antibody targeting delta-like ligand 3 (DLL3). DLL3 is a target that is selectively expressed in small-cell lung cancer (SCLC) tumors, but with minimal normal tissue expression. Tarlatamab has the KDs of 0.64 nM and 0.50 nM for human and nonhuman primate (NHP) DLL3, respectively. Tarlatamab has the KDs of 14.9 nM and 12 nM for human and NHP CD3, respectively. Tarlatamab is a first-in-class HLE BiTE immuno-oncology therapy targeting DLL3 and has the potential for SCLC research[1].

Research Areas >> Cancer

Signaling Pathways >> Stem Cell/Wnt >> Notch

Research Areas >> Inflammation/Immunology

Tarlatamab (AMG-757; 0-10 nM; 48 小时) 在体外对表达 DLL3 的 SCLC 细胞系具有有效的特异性细胞毒活性[1]。 Tarlatamab (0-10 nM; 4-72 小时) 随时间增加颗粒酶 B 水平和细胞毒性，在 48 小时观察到最大信号。T 细胞活化或炎症标志物 CD69、CD71、PD-1 和 PD-L1 (37-39) 被上调[1]。 Cell Viability Assay[1] Cell Line: SCLC cell lines (DMS 79, NCI-H2171, NCI-H889, SHP-77, NCI-H211,COR-L279) Concentration: 0-10 nM Incubation Time: 48 hours Result: AMG 757 effectively engaged human T cells to kill SCLC cell lines, including those with very low DLL3 expression levels.

Tarlatamab (AMG-757; 3 mg/kg; 腹腔给药; 每周一次; 连续三周) 在 SCLC 小鼠模型中驱动肿瘤消退[1]。 Tarlatamab (12 μg/kg; 腹腔给药; 单剂量) 在非人灵长类动物 (NHP) 的平均半衰期为 234 小时 (9.8 天)，平均清除率为 0.487 mL/hour/kg，稳态分布容积为 146 mL/kg[1]。 Animal Model: Female NOD.Cg-PrkdcscidIl2rgtm1Sug/JicTac (NOG) mice with patient-derived SCLC tumor fragments (LXFS 1129 and LXFS 538)[1] Dosage: 3 mg/kg Administration: IP; once weekly for 3 weeks Result: Led to 83% tumor regression and an overall significant reduction in tumor volume compared with that in mice which received a control HLE BiTE molecule in the LXFS 1129 model. Induced 98% tumor regression in the LXFS 538 model.

[1]. Michael J Giffin, et al. AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer. Clin Cancer Res. 2021 Mar 1;27(5):1526-1537.