Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade

• DOI: 10.1038/celldisc.2017.4
• Publication Date: 2017-03-08T14:08:21Z
• Authors: Fei Zhang; Hudie Wei; Xiaoxiao Wang; Yu Bai; Pilin Wang; Jiawei Wu; Xiaoyong Jiang; Yugang Wang; Haiyan Cai; Ting Xu; Aiwu Zhou
• Keywords: Immune checkpoint; Receptor–ligand kinetics; Cancer Immunotherapy

Abstract The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. crystal structures KN035 complexed with PD-L1 free PD-L1, solved here at 1.7 2.7 Å resolution, respectively, show competes PD-1 (programmed death protein 1) for same flat surface on mainly through single loop 21 amino acids. This forms two short helices develops key hydrophobic ionic interactions residues, such as Ile54, Tyr56 Arg113, which are also involved binding. detailed mutagenesis study hotspot residues provides explanation stronger (~1 000-fold) binding than its lack PD-L2. Overall, this reveals how immunoglobulin-variable scaffold or bind either beta-sheet strands; basis designing new checkpoint blockers generating bi-specific combination therapy.