Reference Detail

Ref Type

Journal Article

PMID

(35176764)

Authors

Muik A, Garralda E, Altintas I, Gieseke F, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso PM, Alonso G, Rodriguez-Ruiz ME, Schoedel KB, Blum JM, Sänger B, Salcedo TW, Burm SM, Stanganello E, Verzijl D, Vascotto F, Sette A, Quinkhardt J, Plantinga TS, Toker A, van den Brink EN, Fereshteh M, Diken M, Satijn D, Kreiter S, Breij ECW, Bajaj G, Lagkadinou E, Sasser K, Türeci Ö, Forssmann U, Ahmadi T, Şahin U, Jure-Kunkel M, Melero I

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	12	5	2022 May 02	1248-1265	Cancer Discov

URL

Abstract Text

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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
GEN1046	GEN1046	1	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
GEN1046		GEN-1046\|GEN 1046\|DuoBody-PD-L1x4-1BB\|BNT 311	Immune Checkpoint Inhibitor 149 PD-L1/PD-1 antibody 122	GEN1046 is a bispecific antibody that binds to and simultaneously targets PD-L1 and TNFRSF9 (4-1BB), potentially resulting in T-cell activation leading to increased anti-tumor immune response and decreased tumor growth (PMID: 35176764).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CD274 positive	Advanced Solid Tumor	sensitive	GEN1046	Preclinical	Actionable	In a preclinical study, GEN1046 treatment resulted in T-cell activation and proliferation and induced T-cell-mediated cytotoxicity of CD274 (PD-L1)-positive tumor cells in culture, and induced tumor regression in a transgenic mouse model expressing human CD274 (PD-L1) (PMID: 35176764).	35176764