Publicaciones científicas

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

02-may-2022 | Revista: Cancer Discovery

Alexander Muik  1 , Elena Garralda  2 , Isil Altintas  3 , Friederike Gieseke  1 , Ravit Geva  4 , Eytan Ben-Ami  5 , Corinne Maurice-Dror  6 , Emiliano Calvo  7 , Patricia M LoRusso  8 , Guzman Alonso  2 , Maria E Rodriguez-Ruiz  9 , Kristina B Schoedel  1 , Jordan M Blum  10 , Bianca Sänger  1 , Theodora W Salcedo  10 , Saskia M Burm  3 , Eliana Stanganello  11 , Dennis Verzijl  3 , Fulvia Vascotto  11 , Angelica Sette  3 , Juliane Quinkhardt  1 , Theo S Plantinga  3 , Aras Toker  1 , Edward N van den Brink  3 , Mark Fereshteh  11 , Mustafa Diken  1 , David Satijn  3 , Sebastian Kreiter  1 , Esther C W Breij  3 , Gaurav Bajaj  10 , Eleni Lagkadinou  1 , Kate Sasser  10 , Özlem Türeci  1 , Ulf Forssmann  12 , Tahamtan Ahmadi  10 , Uğur Şahin #  1 , Maria Jure-Kunkel #  10 , Ignacio Melero #  13


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 confer clinical benefit in tumors typically less sensitive to CPIs, GEN1046 may fill a clinical gap in CPI-relapsed or refractory disease or as a combination therapy with CPIs. See related commentary by Li et al., p. 1184. This article is highlighted in the In This Issue feature, p. 1171.

CITA DEL ARTÍCULO  Cancer Discov. 2022 May 2;12(5):1248-1265. doi: 10.1158/2159-8290.CD-21-1345.