PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations

Sun, Xin; Yan, Xiaohong; Zhuo, Wei; Gu, Junping; Zuo, Ke; Liu, Wei; Liang, Li; Gan, Ya; He, Gang; Wan, Hua‐Ping; Gou, Xin; Shi, Hubing; Hu, Jianping

doi:10.3390/ijms19071984

Cited by 31 publications

(23 citation statements)

References 74 publications

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“…118 Notably, KN035 affinity for PD-L1 is ~1000-fold stronger than PD-1's affinity for PD-L1 (IC 50 =5.25 nM). 119 CAR T cells, T cells genetically engineered with MHCindependent recognition of tumor-associated antigens (TAA), have shown increasing benefit in the treatment of hematological malignancy. 120 121 CAR T cells with anti-PD-L1 targeting have demonstrated cytotoxic activity in mice bearing melanoma and colon tumors.…”

Section: Alternative Mechanisms Of Immune Modulation For T Lymphocytementioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

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Immunomodulatory therapies targeting inhibitory checkpoint molecules have revolutionized the treatment of solid tumor malignancies. Concerns about whether systemic administration of an immune checkpoint inhibitor could impact primary brain tumors were answered with the observation of definitive responses in pediatric patients harboring hypermutated gliomas. Although initial clinical results in patients with glioblastoma (GBM) were disappointing, recently published results have demonstrated a potential survival benefit in patients with recurrent GBM treated with neoadjuvant programmed cell death protein 1 blockade. While these findings necessitate verification in subsequent studies, they support the possibility of achieving clinical meaningful immune responses in malignant primary brain tumors including GBM, a disease in dire need of additional therapeutic options. There are several challenges involved in treating glioma with immune checkpoint modulators including the immunosuppressive nature of GBM itself with high inhibitory checkpoint expression, the immunoselective blood brain barrier impairing the ability for peripheral lymphocytes to traffic to the tumor microenvironment and the high prevalence of corticosteroid use which suppress lymphocyte activation. However, by simultaneously targeting multiple costimulatory and inhibitory pathways, it may be possible to achieve an effective antitumoral immune response. To this end, there are now several novel agents targeting more recently uncovered “second generation” checkpoint molecules. Given the multiplicity of drugs being considered for combination regimens, an increased understanding of the mechanisms of action and resistance combined with more robust preclinical and early clinical testing will be needed to be able to adequately test these agents. This review summarizes our current understanding of T lymphocyte-modulating checkpoint molecules as it pertains to glioma with the hope for a renewed focus on the most promising therapeutic strategies.

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Section: Alternative Mechanisms Of Immune Modulation For T Lymphocytementioning

confidence: 99%

T lymphocyte-targeted immune checkpoint modulation in glioma

Kelly

Giles

Gilbert

2020

J Immunother Cancer

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“…After minimization and equilibration, MD simulations for the different systems were performed, respectively. Three hundred and fifty nanoseconds of MD simulations were run under periodic boundary conditions using NPT ensemble at 300 K (Sun et al, 2018.…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Characterizing the Binding Sites for GK Domain of DLG1 and DLG4 via Molecular Dynamics Simulation

Chen

Shan

et al. 2020

Front. Mol. Biosci.

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Discs-large (DLG) is a member that belongs to the membrane-associated guanylate kinase (MAGUK) family. The GK domain of DLGs has evolved into a protein-protein interaction module that could bind with kinds of proteins to regulate diverse cellular functions. Previous reports have demonstrated the GK domain of DLGs functioned as a phosphor-peptide-binding module by resolving the crystal structures. Here we investigated into the interactions of DLG1 and DLG4 with their reported phosphor-peptides by molecular dynamics simulations. Post-dynamics analysis showed that DLG1/4 formed extensive interactions with phosphorylated ligands, including hydrophobic and hydrogen bonding interactions. Among them, the highly conserved residues among the DLGs in phosphor-site and β5 sheet were crucial for the binding according to the energy decomposition calculations. Additionally, the binding interactions between DLG4 and reported unphosphorylated peptides including MAP1A and designed GK inhibitory (GKI-QSF) peptides were analyzed. We found the key residues that played important roles in DLG4/unphosphorylated peptide systems were very similar as in DLG4/phosphor-peptide systems. Moreover, the molecular dynamic simulation for the complex of DLG1 and GKI-QSF was carried out and predicted that the GKI-QSF could bind with DLG1 with similar Kd value compared to DLG4/GKI-QSF, which was verified by using ITC assay (Kd = 1.20 ± 0.29 µM). Our study might be helpful for the better understanding of the structural and biological function of DLGs GK domain and encourage the discovery of new binders.

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“…These studies again highlight that the necessity to modulate the nanobody format should be evaluated on a per case basis. Therapeutic nanobodies have also been developed against the ICP PD-L1 in order to counteract immune inhibition through the ligation with its receptor PD-1 that is highly expressed on activated T cells 111,198-200. Nanobody mediated blockade of PD-L1, present on DCs, could significantly increase the activity of T cells upon antigen presentation, an effect that was not seen with the FDA-approved anti-PD-L1 antibody Avelumab 198.…”

Section: Therapeutic Application Of Nanobodies and Nanobody Derivativmentioning

confidence: 99%

Theranostics in immuno-oncology using nanobody derivatives

Lecocq

Vlaeminck

Hanssens³

et al. 2019

Theranostics

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Targeted therapy and immunotherapy have become mainstream in cancer treatment. However, only patient subsets benefit from these expensive therapies, and often responses are short‐lived or coincide with side effects. A growing modality in precision oncology is the development of theranostics, as this enables patient selection, treatment and monitoring. In this approach, labeled compounds and an imaging technology are used to diagnose patients and select the best treatment option, whereas for therapy, related compounds are used to target cancer cells or the tumor stroma. In this context, nanobodies and nanobody-directed therapeutics have gained interest. This interest stems from their high antigen specificity, small size, ease of labeling and engineering, allowing specific imaging and design of therapies targeting antigens on tumor cells, immune cells as well as proteins in the tumor environment. This review provides a comprehensive overview on the state-of-the-art regarding the use of nanobodies as theranostics, and their importance in the emerging field of personalized medicine.

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PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations

Cited by 31 publications

References 74 publications

T lymphocyte-targeted immune checkpoint modulation in glioma

T lymphocyte-targeted immune checkpoint modulation in glioma

Characterizing the Binding Sites for GK Domain of DLG1 and DLG4 via Molecular Dynamics Simulation

Theranostics in immuno-oncology using nanobody derivatives

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