High‐affinity <scp>PD</scp>‐1 molecules deliver improved interaction with <scp>PD</scp>‐L1 and <scp>PD</scp>‐L2

Li, Yanyan; Liang, Zhongxin; Tian, Ye; Cai, Wenxuan; Weng, Zhiming; Chen, Lin; Zhang, Huanling; Bao, Yifeng; Zhang, Hongjun; Zeng, Si-Hai; Bei, Chunhua; Li, Yang

doi:10.1111/cas.13666

Cited by 25 publications

(10 citation statements)

References 48 publications

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“…2 F and G ). The A132V mutant has higher affinity for PD-L1, consistent with previous reports (21, 29–31), but the N74G and T76P single mutants have minor effects (Fig. 2 F and G and SI Appendix , Fig.…”

Section: Resultssupporting

confidence: 91%

A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery

Tang

Kim

2019

Proc. Natl. Acad. Sci. U.S.A.

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Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC′ and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1’s affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC′ and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC′ loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.

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Section: Resultssupporting

confidence: 91%

A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery

Tang

Kim

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Consequently, these results support the protein affinity to its designed targets, appearing as an interesting option in the inflammatory animal models addressed in the present study. Despite the reported similar KD values of the CD80 and HYBRI CTLA4 interaction, the KD values of the PD-1 and HYBRI’s PD-L2 interaction are higher than the values found in the literature [ 31 , 49 , 50 , 51 , 52 ]. Similarly to the increased affinity of the modified PD-L2 described by Philips et al [ 51 ], PD-L2 molecules in the HYBRI construct may have suffered conformational changes, which might account for its increased binding to PD-1.…”

Section: Discussioncontrasting

confidence: 78%

Dual and Opposite Costimulatory Targeting with a Novel Human Fusion Recombinant Protein Effectively Prevents Renal Warm Ischemia Reperfusion Injury and Allograft Rejection in Murine Models

Guiteras

Ramon

Crespo

et al. 2021

IJMS

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Many studies have shown both the CD28—D80/86 costimulatory pathway and the PD-1—PD-L1/L2 coinhibitory pathway to be important signals in modulating or decreasing the inflammatory profile in ischemia-reperfusion injury (IRI) or in a solid organ transplant setting. The importance of these two opposing pathways and their potential synergistic effect led our group to design a human fusion recombinant protein with CTLA4 and PD-L2 domains named HYBRI. The objective of our study was to determine the HYBRI binding to the postulated ligands of CTLA4 (CD80) and PD-L2 (PD-1) using the Surface Plasmon Resonance technique and to evaluate the in vivo HYBRI effects on two representative kidney inflammatory models—rat renal IRI and allogeneic kidney transplant. The Surface Plasmon Resonance assay demonstrated the avidity and binding of HYBRI to its targets. HYBRI treatment in the models exerted a high functional and morphological improvement. HYBRI produced a significant amelioration of renal function on day one and two after bilateral warm ischemia and on days seven and nine after transplant, clearly prolonging the animal survival in a life-sustaining renal allograft model. In both models, a significant reduction in histological damage and CD3 and CD68 infiltrating cells was observed. HYBRI decreased the circulating inflammatory cytokines and enriched the FoxP3 peripheral circulating, apart from reducing renal inflammation. In conclusion, the dual and opposite costimulatory targeting with that novel protein offers a good microenvironment profile to protect the ischemic process in the kidney and to prevent the kidney rejection, increasing the animal’s chances of survival. HYBRI largely prevents the progression of inflammation in these rat models.

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“…Our results were opposite to the initial hypothesis based on the potential of sPD-1 to act as a checkpoint-inhibitor-like protein by binding to mPD-L1 and mPD-L2. Supporting our finding, natural sPD-1 was shown to have a low binding affinity to mPD-L1 and mPD-L2 [37], and therefore high-affinity PD-1 molecules were developed [38]. Thus, it seems likely that although sPD-1 levels are high prior to treatment, they do not translate to a similar outcome as checkpoint inhibitors due to weak sPD-1 binding affinity.…”

Section: Discussionsupporting

confidence: 73%

Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma

Vajavaara

Mortensen

Leivonen

et al. 2021

Cancers

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Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12–7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16–6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL.

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High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2

Cited by 25 publications

References 48 publications

A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery

A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery

Dual and Opposite Costimulatory Targeting with a Novel Human Fusion Recombinant Protein Effectively Prevents Renal Warm Ischemia Reperfusion Injury and Allograft Rejection in Murine Models

Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma

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