Supplementary Table from The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner

Peper-Gabriel, Janet K.; Pavlidou, Marina; Pattarini, Lucia; Morales-Kastresana, Aizea; Jaquin, Thomas J.; Gallou, Catherine; Hansbauer, Eva-Maria; Richter, Marleen; Lelievre, Helene; Scholer-Dahirel, Alix; Bossenmaier, Birgit; Sancerne, Celine; Riviere, Matthieu; Grandclaudon, Maximilien; Zettl, Markus; Bel Aiba, Rachida S.; Rothe, Christine; Blanc, Veronique; Olwill, Shane A.

doi:10.1158/1078-0432.22482111.v1

ccr-21-2762_supplementary_table_1_suppst1.pdf (48.77 kB)

Supplementary Table from The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner

journal contribution

posted on 2023-03-31, 23:01 authored by Janet K. Peper-Gabriel, Marina Pavlidou, Lucia Pattarini, Aizea Morales-Kastresana, Thomas J. Jaquin, Catherine Gallou, Eva-Maria Hansbauer, Marleen Richter, Helene Lelievre, Alix Scholer-Dahirel, Birgit Bossenmaier, Celine Sancerne, Matthieu Riviere, Maximilien Grandclaudon, Markus Zettl, Rachida S. Bel Aiba, Christine Rothe, Veronique Blanc, Shane A. Olwill

Supplementary Table from The PD-L1/4-1BB Bispecific Antibody–Anticalin Fusion Protein PRS-344/S095012 Elicits Strong T-Cell Stimulation in a Tumor-Localized Manner

History

ARTICLE ABSTRACT

While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability of response. A bispecific molecule that blocks the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis and localizes 4-1BB costimulation to a PD-L1–positive (PD-L1+) tumor microenvironment (TME) or tumor draining lymph nodes could maximize antitumor immunity and increase the therapeutic window beyond what has been reported for anti–4-1BB mAbs. We generated and characterized the PD-L1/4-1BB bispecific molecule PRS-344/S095012 for target binding and functional activity in multiple relevant in vitro assays. Transgenic mice expressing human 4-1BB were transplanted with human PD-L1–expressing murine MC38 cells to assess in vivo antitumoral activity. PRS-344/S095012 bound to its targets with high affinity and efficiently blocked the PD-1/PD-L1 pathway, and PRS-344/S095012-mediated 4-1BB costimulation was strictly PD-L1 dependent. We demonstrated a synergistic effect of both pathways on T-cell stimulation with the bispecific PRS-344/S095012 being more potent than the combination of mAbs. PRS-344/S095012 augmented CD4-positive (CD4+) and CD8-positive (CD8+) T-cell effector functions and enhanced antigen-specific T-cell stimulation. Finally, PRS-344/S095012 demonstrated strong antitumoral efficacy in an anti–PD-L1–resistant mouse model in which soluble 4-1BB was detected as an early marker for 4-1BB agonist activity. The PD-L1/4-1BB bispecific PRS-344/S095012 efficiently combines checkpoint blockade with a tumor-localized 4-1BB–mediated stimulation burst to antigen-specific T cells, more potent than the combination of mAbs, supporting the advancement of PRS-344/S095012 toward clinical development.See related commentary by Shu et al., p. 3182