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

作者：Alexander Muik, Elena Garralda, Işıl Altıntaş, Friederike Gieseke, Ravit Geva, Eytan Ben‐Ami, Corinne Maurice‐Dror, Emiliano Calvo, Patricia Mucci LoRusso, Guzmán Alonso, Maria Esperanza Rodriguez-Ruiz, Kristina B. Schoedel, Jordan M. Blum, Bianca Sänger, Theodora W. Salcedo, Saskia Maria Burm, Eliana Stanganello, Dennis Verzijl, Fulvia Vascotto, Angelica Sette, Juliane Quinkhardt, Theo S. Plantinga, Aras Toker, Edward N. van den Brink, Mark Fereshteh, Mustafa Diken, David P. E. Satijn, Sebastian Kreiter, Esther C.W. Breij, Gaurav Bajaj, Eleni Lagkadinou, Kate Sasser, Özlem Türeci, Ulf Forssmann, Tahamtan Ahmadi, Uğur Şahin, Maria Jure‐Kunkel, Ignacio Melero · 发表于：Cancer Discovery · 年份：2022 · DOI：10.1158/2159-8290.cd-21-1345 · 被引用次数：123 · 研究领域：Cancer Immunotherapy and Biomarkers、Monoclonal and Polyclonal Antibodies Research、CAR-T cell therapy research

Checkpoint inhibitors (CPI) 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 programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis by activating cytotoxic T-cell-mediated antitumor immunity. DuoBody-PD-L1×4-1BB (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. SIGNIFICANCE: DuoBody-PD-L1×4-1BB (GEN1046) is a first-in-class bispecific immunotherapy with a manageable safety profile and encouraging preclinical and early clinical activity. With its ability to co...