The FG Loop of PD-1 Serves as a “Hotspot” for Therapeutic Monoclonal Antibodies in Tumor Immune Checkpoint Therapy

Chen, Danqing; Tan, Shuguang; Zhang, Hao; Wang, Haiyuan; He, Wei-Wu; Tong, Zhou; Zhu, Jianhua; Cheng, Hao; Gao, Shan; Chai, Yan; Qi, Jianxun; Xiao, Mingzhong; Yan, Jinghua; Gao, George F.

doi:10.1016/j.isci.2019.03.017

Cited by 38 publications

(56 citation statements)

References 37 publications

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“…To date, five PD-1/Mab complex structures have been reported, including PD-1/nivolumab Fab 24,26 , PD-1/pembrolizumab Fab 23–25 , and three other PD-1/Fabs 28,29 . Previous studies have shown that each PD-1 Mab exhibits different binding modality to PD-1.…”

Section: Resultsmentioning

confidence: 99%

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Identification of a monoclonal antibody that targets PD-1 in a manner requiring PD-1 Asn58 glycosylation

Wang

Wang³

et al. 2019

Commun Biol

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Programmed cell death 1 (PD-1) is inhibitory receptor and immune checkpoint protein.Blocking the interaction of PD-1 and its ligands PD-L1/ L2 is able to active T-cell-mediated antitumor response. Monoclonal antibody-based drugs targeting PD-1 pathway have exhibited great promise in cancer therapy. Here we show that MW11-h317, an anti-PD-1 monoclonal antibody, displays high affinity for PD-1 and blocks PD-1 interactions with PD-L1/L2. MW11-h317 can effectively induce T-cell-mediated immune response and inhibit tumor growth in mouse model. Crystal structure of PD-1/MW11-h317 Fab complex reveals that both the loops and glycosylation of PD-1 are involved in recognition and binding, in which Asn58 glycosylation plays a critical role. The unique glycan epitope in PD-1 to MW11-h317 is different from the first two approved clinical PD-1 antibodies, nivolumab and pembrolizumab. These results suggest MW11-h317 as a therapeutic monoclonal antibody of PD-1 glycosylation-targeting which may become efficient alternative for cancer therapy.

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Section: Resultsmentioning

confidence: 99%

“…In that study, authors demonstrated that N-glycosylation of PD-1 did not affect the binding affinity to nivolumab 26 . Recently, there were two reports about MAbs targeting PD-1, in which the binding modes were also glycosylation-independent 28,29 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a monoclonal antibody that targets PD-1 in a manner requiring PD-1 Asn58 glycosylation

Wang

Wang³

et al. 2019

Commun Biol

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“…In contrast, PD-1 glycosylation is not essential for PD-1/PD-L1 interaction. Structure studies revealed that PD-1 glycosylation sites are located away from PD-1/PD-L1–binding interface, suggesting that modifications of PD-1 glycosylation would not have direct influence on this interaction ( 23 ). Consistently, binding of the therapeutic blocking antibodies nivolumab and pembrolizumab to PD-1 was independent of PD-1 glycosylation ( 24 , 25 ).…”

Section: Expression Of Pd-1 and Its Ligandsmentioning

confidence: 99%

Revisiting the PD-1 pathway

et al. 2020

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Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

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“…The FG and BC loops locate on the IgV domain. Previous studies showed that the FG loop (i.e., PD– 1 PRO130 and PD– 1 LYS131) is a binding site for PD-L1 as well as a “hot spot” for several immune checkpoint blockade monoclonal antibodies, such as GY-5 and GY-14 ( Zak et al, 2015 ; Liu and Liu, 2017 ; Chen et al, 2019a ). They clearly suggest a steric clash blockade mechanism of nivolumab.…”

Section: Introductionmentioning

confidence: 99%

Investigating the Role of the N-Terminal Loop of PD-1 in Binding Process Between PD-1 and Nivolumab via Molecular Dynamics Simulation

Liu

Jin

Chen

et al. 2020

Front. Mol. Biosci.

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The blockade of immune checkpoints, such as programmed death receptor 1 (PD-1) and programmed death ligand 1 protein (PD-L1), is a promising therapeutic approach in cancer immunotherapy. Nivolumab, a humanized IgG4 antibody targeting PD-1, was approved by the US Food and Drug Administration for several cancers in 2014. Crystal structures of the nivolumab/PD-1 complex show that the epitope of PD-1 locates at the IgV domain (including the FG and BC loops) and the N-terminal loop. Although the N-terminal loop of PD-1 has been shown to play a dominant role in the complex interface of the static structure, its role in the dynamic binding process has not been illustrated clearly. Here, eight molecular systems were established for nivolumab/PD-1 complex, and long-time molecular dynamics simulations were performed for each. Results showed that the N-terminal loop of PD-1 prefers to bind with nivolumab to stabilize the interface between IgV and nivolumab. Furthermore, the binding of the N-terminal loop with nivolumab induces the rebinding between the IgV domain and nivolumab. Thus, we proposed a two-step binding model for the nivolumab/PD-1 binding, where the interface switches to a high-affinity state with the help of the N-terminal loop. This finding suggests that the N-terminal loop of PD-1 might be a potential target for anti-PD-1 antibody design, which could serve as an important gatekeeper for the anti-PD-1 antibody binding.

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The FG Loop of PD-1 Serves as a “Hotspot” for Therapeutic Monoclonal Antibodies in Tumor Immune Checkpoint Therapy

Cited by 38 publications

References 37 publications

Identification of a monoclonal antibody that targets PD-1 in a manner requiring PD-1 Asn58 glycosylation

Identification of a monoclonal antibody that targets PD-1 in a manner requiring PD-1 Asn58 glycosylation

Revisiting the PD-1 pathway

Investigating the Role of the N-Terminal Loop of PD-1 in Binding Process Between PD-1 and Nivolumab via Molecular Dynamics Simulation

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