An Fc-inert PD-L1×4-1BB bispecific antibody mediates potent anti-tumor immunity in mice by combining checkpoint inhibition and conditional 4-1BB co-stimulation

OncoImmunology

Tahamtan Ahmadi¹  Dennis Verzijl¹  David P.E. Satijn¹  Friederike Gieseke²  David Eisel²  Christian Grunwitz²  Mustafa Diken²  Aras Toker²  Alexander Muik²  Kristina B Schoedel²  Lena M Kranz²  Sebastian Kreiter²  Ugur Sahin²  Özlem Türeci²  Mathias Vormehr²  Saskia M Burm³  Isil Altintas³  Esther C.W. Breij³  Theodora W. Salcedo⁴  Maria Jure-Kunkel⁴  Kate Sasser⁴ 

[1] ;BioNTech SE;Genmab, Utrecht, The Netherlands;Genmab;

关键词: pd-l1;    4-1bb;    bispecific antibody;    checkpoint immunotherapy;    t cells;   

DOI  :  10.1080/2162402X.2022.2030135

来源: DOAJ

【 摘 要 】

Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis have changed the treatment paradigm for advanced solid tumors; however, many patients experience treatment resistance. In preclinical models 4-1BB co-stimulation synergizes with ICI by activating cytotoxic T- and NK-cell-mediated anti-tumor immunity. Here we characterize the mechanism of action of a mouse-reactive Fc-inert PD-L1×4-1BB bispecific antibody (mbsAb-PD-L1×4-1BB) and provide proof-of-concept for enhanced anti-tumor activity. In reporter assays mbsAb-PD-L1×4-1BB exhibited conditional 4-1BB agonist activity that was dependent on simultaneous binding to PD-L1. mbsAb-PD-L1×4-1BB further blocked the PD-L1/PD-1 interaction independently of 4-1BB binding. By combining both mechanisms, mbsAb-PD-L1×4-1BB strongly enhanced T-cell proliferation, cytokine production and antigen-specific cytotoxicity using primary mouse cells in vitro. Furthermore, mbsAb-PD-L1×4-1BB exhibited potent anti-tumor activity in the CT26 and MC38 models in vivo, leading to the rejection of CT26 tumors that were unresponsive to PD-L1 blockade alone. Anti-tumor activity was associated with increased tumor-specific CD8+ T cells and reduced regulatory T cells within the tumor microenvironment and tumor-draining lymph nodes. In immunocompetent tumor-free mice, mbsAb-PD-L1×4-1BB treatment neither induced T-cell infiltration into the liver nor elevated liver enzymes in the blood. Dual targeting of PD-L1 and 4-1BB with a bispecific antibody may therefore address key limitations of first generation 4-1BB-agonistic antibodies, and may provide a novel approach to improve PD-1/PD-L1 checkpoint blockade.

【 授权许可】

Unknown