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

The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field of cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. The crystal structures of KN035 complexe...

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Published in:Cell discovery Vol. 3; no. 1; p. 17004
Main Authors: Zhang, Fei, Wei, Hudie, Wang, Xiaoxiao, Bai, Yu, Wang, Pilin, Wu, Jiawei, Jiang, Xiaoyong, Wang, Yugang, Cai, Haiyan, Xu, Ting, Zhou, Aiwu
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 07-03-2017
Springer Nature B.V
Nature Publishing Group
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Summary:The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field of cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. The crystal structures of KN035 complexed with PD-L1 and free PD-L1, solved here at 1.7 and 2.7 Å resolution, respectively, show that KN035 competes with PD-1 (programmed death protein 1) for the same flat surface on PD-L1, mainly through a single surface loop of 21 amino acids. This loop forms two short helices and develops key hydrophobic and ionic interactions with PD-L1 residues, such as Ile54, Tyr56 and Arg113, which are also involved in PD-1 binding. The detailed mutagenesis study identified the hotspot residues of the PD-L1 surface and provides an explanation for the stronger (~1 000-fold) binding of KN035 to PD-L1 than PD-1 and its lack of binding to PD-L2. Overall, this study reveals how a single immunoglobulin-variable scaffold of KN035 or PD-1 can bind to a flat protein surface through either a single surface loop or beta-sheet strands; and provides a basis for designing new immune checkpoint blockers and generating bi-specific antibodies for combination therapy.
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These authors contributed equally to this work.
FZ, HW, JW, XJ, YW and HC prepared all the PD-L1 mutants, assessed the binding affinity of PD-L1 and solved the structures. XW, YB and PW screened the anti-PD-L1 antibodies and performed the in vivo experiments. HC, TX and AZ designed all the experiments and wrote the paper.
ISSN:2056-5968
2056-5968
DOI:10.1038/celldisc.2017.4