靶向PD-L1和4-1BB (GEN1046)的双特异性抗体

2022-04-28 12:22

在人T细胞培养中，GEN1046诱导T细胞增殖、细胞因子产生和抗原特异性T细胞介导的细胞毒性优于临床批准的PD-(L)1抗体，并在可移植小鼠肿瘤模型中发挥了强大的抗肿瘤活性。

Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients With Advanced Refractory Solid Tumors.

(Cancer Discov, IF:39.397)

Muik A, Garralda E, Altintas I, et al. Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients With Advanced Refractory Solid Tumors[J]. Cancer Discov, 2022.

Checkpoint inhibitors (CPIs) have revolutionized the treatment paradigm for advanced solid tumors; however, there remains an opportunity to improve response rates and outcomes. In preclinical models, 4-1BB costimulation synergizes with CPIs targeting the PD-1/PD-L1 axis by activating cytotoxic T-cell-mediated antitumor immunity. DuoBody(R)-PD-L1x4-1BB (GEN1046) is an investigational, first-in-class, bispecific immunotherapy agent designed to act on both pathways by combining simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell-mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity (disease control rate: 65.6% [40/61]), including patients resistant to prior PD-(L)1 immunotherapy.

检查点抑制剂(CPIs)已经彻底改变了晚期实体肿瘤的治疗模式;然而，仍有机会提高反应率和结果。在临床前模型中，4-1BB共刺激通过激活细胞毒性T细胞介导的抗肿瘤免疫，与靶向PD-1/PD-L1轴的CPIs协同作用。DuoBody(R)-PD-L1x4-1BB (GEN1046)是一种尚在研究中的、首创的双特异性免疫治疗药物，通过同时互补的PD-L1阻断和条件4-1BB刺激在一个分子中发挥作用。

在人T细胞培养中，GEN1046诱导T细胞增殖、细胞因子产生和抗原特异性T细胞介导的细胞毒性优于临床批准的PD-(L)1抗体，并在可移植小鼠肿瘤模型中发挥了强大的抗肿瘤活性。正在进行的首次在多重治疗后的晚期难治性实体瘤患者身上进行的剂量递增研究(NCT03917381)中，GEN1046在外周血中显示了与其作用机制一致的药效学免疫效应，可管理的安全性和早期临床活性(疾病控制率:65.6%[40/61])，包括对既往PD-(L)1免疫治疗耐药的患者。