Merck will pay $680 million to acquire Harpoon Therapeutics, a clinical-stage immuno-oncology company developing a new class of off-the-shelf T cell engager therapies for solid tumors. The acquisition gives the big pharma access to Harpoon’s portfolio of T cell engager agents, and to the biotech’s platforms to manufacture trispecific T cell engager therapies. T cell engagers are engineered proteins with two or more binding domains designed to physically redirect T cells to attack and lyse tumor cells. In the case of bispecific T cell engagers, one arm targets an antigen on a cancer cell and another acts as a trigger molecule on T cells, targeting CD3. The approved T cell engagers, such as Blincyto (blinatumomab), Columvi (glofitamab), Lunsumio (mosunetuzumab) and Talvey (talquetamab), are all bispecific. Harpoon’s so-called trispecific T-cell-activating construct (TriTACs) are designed with three binding domains, with the third added to bind human serum albumin to improve half-life. TriTACs, at around 50 kDa, are smaller than monoclonal antibodies, which may boost tumor penetration. Some TriTACs are engineered as prodrugs; they only become activated once they reach the tumor. The company’s lead molecule is HPN328, which targets delta-like ligand 3 (DLL3), an inhibitory Notch ligand highly expressed in cancers such as small cell lung cancer (SCLC). Preliminary clinical data showed that the trispecific molecule shrank tumors in 48% of patients with SCLC and 54% of patients with other tumor types. DLL3 is also the target of Amgen’s bispecific T cell engager tarlatamab, which is in a phase 3 trial for SCLC. Merck also gets clinical-stage HPN217, which targets B cell maturation antigen, and preclinical HPN601, which targets epithelial cell adhesion molecule. The pharma’s deal with Harpoon builds on a 2020 partnership with Janux Therapeutics that gave Merck access to another T cell engager platform, dubbed TRACTr, to identify tumor-activated T cell engagers.

默克公司将斥资 6.8 亿美元收购 Harpoon Therapeutics，这是一家临床阶段的免疫肿瘤公司，开发一种新型现成的实体瘤 T 细胞接合疗法。此次收购使这家大型制药公司能够获得 Harpoon 的 T 细胞接合剂产品组合，以及该生物技术公司的平台来制造三特异性 T 细胞接合疗法。 T 细胞接合剂是具有两个或多个结合域的工程蛋白，旨在物理重定向 T 细胞以攻击和裂解肿瘤细胞。在双特异性 T 细胞接合器的情况下，一只臂靶向癌细胞上的抗原，另一只臂充当 T 细胞上的触发分子，靶向 CD3。批准的 T 细胞接合剂，如 Blincyto (blinatumomab)、Columvi (glofitamab)、Lunsumio (mosunetuzumab) 和 Talvey (talquetamab) 都是双特异性的。 Harpoon 所谓的三特异性 T 细胞激活结构 (TriTAC) 设计有三个结合域，其中添加第三个结合域以结合人血清白蛋白以延长半衰期。 TriTAC 的分子量约为 50 kDa，比单克隆抗体小，这可能会促进肿瘤渗透。一些 TriTAC 被设计为前药；它们只有在到达肿瘤后才会被激活。该公司的主导分子是 HPN328，其目标是 δ 样配体 3 (DLL3)，这是一种在小细胞肺癌 (SCLC) 等癌症中高度表达的抑制性 Notch 配体。初步临床数据显示，三特异性分子使 48% 的 SCLC 患者和 54% 的其他肿瘤类型患者的肿瘤缩小。 DLL3 也是安进双特异性 T 细胞接合剂 tarlatamab 的靶标，该药物正处于 SCLC 的 3 期试验中。默克还获得了针对 B 细胞成熟抗原的临床阶段 HPN217 和针对上皮细胞粘附分子的临床前 HPN601。该制药公司与 Harpoon 的交易建立在 2020 年与 Janux Therapeutics 的合作伙伴关系之上，该合作关系使默克能够使用另一个名为 TRACTr 的 T 细胞接合器平台，以识别肿瘤激活的 T 细胞接合器。