Combination of two novel blocking antibodies, anti-PD-1 antibody ezabenlimab (BI 754091) and anti-LAG-3 antibody BI 754111, leads to increased immune cell responses

• DOI: 10.1080/2162402x.2022.2080328
• Publication Date: 2022-06-16T13:59:02Z
• Authors: Markus Zettl; Melanie Wurm; Otmar Schaaf; Sven Mostböck; Iñigo Tirapu; Ilse Apfler; Ivo C. Lorenz; Lee Frego; Cynthia Kenny; Michael Thibodeau; Elisa Oquendo Cif...; Markus Reschke; Jürgen Moll; Norbert Kraut; Anne Vogt; Jonathon D. Sedgwick; Irene C. Waizenegger
• Keywords: Blocking antibody

Upregulation of inhibitory receptors, such as lymphocyte activation gene-3 (LAG-3), may limit the antitumor activity therapeutic antibodies targeting programmed cell death protein-1 (PD-1) pathway. We describe binding properties ezabenlimab, an anti-human PD-1 antibody, and BI 754111, LAG-3 assess their alone in combination. Ezabenlimab bound with high affinity to human (KD = 6 nM) blocked interaction PD-L1 PD-L2. dose-dependently increased interferon-γ secretion T cells expressing co-culture PD-L1-expressing dendritic cells. Administration ezabenlimab knock-in mice inhibited growth MC38 tumors. To reduce immunogenicity, was reformatted from a IgG4 chimeric variant mouse IgG1 backbone (BI 905725) for further vivo studies. Combining 905725 anti-mouse improved versus monotherapy tumor model. generated which prevented its ligand, major histocompatibility complex class II. In vitro model antigen-experienced memory LAG-3, by average 1.8-fold isotype control (p 0.027) 754111 monotherapy, 6.9-fold < 0.0001) 13.2-fold plus ezabenlimab. Overall, respective targets ligand binding. enhanced supporting clinical investigation this combination (NCT03156114; NCT03433898).