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.

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

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© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.

Déclaration de conflit d'intérêts

U.S. and Ö.T. are management board members and employees at BioNTech SE (Mainz, Germany); A.M., F.G., K.S., A.T., D.E., L.M.K., M.V., M.D. and S.K. are employees at BioNTech SE. Some of the authors have securities from BioNTech SE. I.A., S.M.B., T.W.S., D.V., D.P.E.S., K.S., T.A., E.C.W.B., and M.J. are employees at Genmab and own stock and/or stock options. I.A., D.P.E.S., U.S., A.M., F.G. and C.G. are inventors on patents and patent applications related to PD-L1×4-1BB bispecific antibodies.