Virtual Screening and In Vitro Evaluation of PD-L1 Dimer Stabilizers for Uncoupling PD-1/PD-L1 Interaction from Natural Products (original) (raw)
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PD 1: A Trending Target in Anti-cancer Research
Biointerface Research in Applied Chemistry, 2023
Cancer has been identified as a major cause of mortality around the world fora long. To improve the recovery rates of cancer patients, the development of more effective chemopreventive techniques and treatment methods has become important day by day. Recently, various immune inhibitors, mainly including anti-PD-1 and anti-PDL-1, derived from single cells of monoclonal antibodies, have emerged for a group of cancer patients. Functions of T-cells and tumor-infiltrating lymphocytes (TIL) are suppressed by PD-1 and PDLs, while the function of immunosuppressive regulatory T-cells (Tregs) is increased by the latter. To summarize the role of PD-1 and PDLs immune inhibitors in immuno-oncology (I-O), a huge literature survey has been carried out in Science Direct, Scopus, Pubmed, and various other literature hubs for collection of data. This article is focused on cancer immunotherapy, the mechanism of action of PD-1 and PDLs as immune inhibitors, combinatorial immunotherapy, and various FDA approved target anticancer drugs working against PD-1 and PDLs, a very novel and important target in the field of personalized anticancer drug delivery. Further, there is a wide scope for cancer researchers in this area to explore in the near future.
Molecular Cancer Therapeutics, 2019
Pioneering success of antibodies targeting immune checkpoints such as PD-1 and CTLA4 has opened novel avenues for cancer immunotherapy. Along with impressive clinical activity, severe immune-related adverse events (irAE) due to the breaking of immune self-tolerance are becoming increasingly evident in antibody-based approaches. As a strategy to better manage severe adverse effects, we set out to discover an antagonist targeting PD-1 signaling pathway with a shorter pharmacokinetic profile. Herein, we describe a peptide antagonist NP-12 that displays equipotent antagonism toward PD-L1 and PD-L2 in rescue of lymphocyte proliferation and effector functions. In preclinical models of melanoma, colon cancer, and kidney cancers, NP-12 showed significant efficacy comparable with commercially available PD-1–targeting antibodies in inhibiting primary tumor growth and metastasis. Interestingly, antitumor activity of NP-12 in a preestablished CT26 model correlated well with pharmacodynamic effe...
Seven different anti-PD-1 and PD-L1 monoclonal antibodies are now widely used in the US to treat a variety of cancer types, but there have been no clinical trials comparing them directly. Furthermore, because many of these antibodies do not cross react between mouse and human proteins, no preclinical models exist in which to consider these types of questions. Thus, we produced humanized PD-1 and PD-L1 mice in which the extracellular domains of both mouse PD-1 and PD-L1 were replaced with the corresponding human sequences. Using this new model, we sought to compare the strength of the immune response generated by FDA-approved antibodies. To do this, we performed an in vivo T cell priming assay in which anti-PD-1/L1 therapies were given at the time of T cell priming against surrogate tumor antigen (OVA), followed by subsequent B16-OVA tumor challenge. We found that anti-PD-1/L1-treated mice exhibited significantly better tumor rejection than controls, although both the control and ant...
PD-L1 Distribution and Perspective for Cancer Immunotherapy—Blockade, Knockdown, or Inhibition
Frontiers in Immunology
Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.
Comprehensive in vitro characterization of PD-L1 small molecule inhibitors
Scientific Reports
Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies have individually disclosed several promising PD-1/PD-L1 inhibitors, whose detailed experimental data are not publicly disclosed. In this work, we report the rigorous and systematic in vitro characterization of a selected set of potent PD-1/PD-L1 macrocyclic peptide (BMSpep-57) and small-molecule inhibitors (BMS-103, BMS-142) from BMS and a peptidomimetic small-molecule inhibitor from Aurigene (Aurigene-1) using a series of biochemical and cell-based assays. Our results confirm that BMS-103 and BMS-142 are strongly active in biochemical assays; however, their acute cytotoxicity greatly compromised their immunological activity. On the other hand, Aurigene-1 did not show any activity in both biochemical and immunological assays. Furthermore, we also report the discovery of a small-molecule immune modulator, whose mode-of-action is not clear; however, it exhibits favorable drug-like properties and strong immunological activity. We hope that the results presented here will be useful in guiding the development of next-generation PD-1/PD-L1 small molecule inhibitors. From the initial efforts of William Coley 1-3 , who demonstrated that treatment with live bacteria or bacterial products (Coley toxins) could regress tumors, in late 1800s to the recent Nobel Prize award to James Allison and Tasuku Honjo, for their discoveries of key immune checkpoints proteins 4 , cancer immunotherapy has come a long way. Today, immunotherapy has emerged as a powerful strategy for treating various types of cancers. This has become possible due to significant advances in our understanding about the molecular mechanisms behind the growth of cancers and their interplay with the host immune system, particularly the one mediated by T-lymphocytes (T cells). T cells play a pivotal role in controlling the adaptive immune response against pathogens 5 and in autoimmunity 6. Upon activation, T cells mediate various cellular immune responses against pathogens such as chronic viral infections 7-11. On the other hand, there is a class of negative immune modulatory molecules (called the
Rational Design and Development of a Peptide Inhibitor for the PD-1/PD-L1 Interaction
Cancer letters, 2018
We report here the rational design and validation of a peptide inhibitor to the PD-1/PD-L1 interaction as an attempt to develop a viable alternative to current inhibitory antibodies. We demonstrated, by biolayer interferometry and in silico docking simulations, that a PD-L1 peptide mimetic (PL120131) can interfere with the PD-1/PD-L1 interaction by binding to PD-1. We show that PL120131 is capable of inhibiting PD-1 mediated apoptotic signaling pathway and rescuing Jurkat cells and primary lymphocytes from apoptosis. Additionally, we show that PL120131 treatment allows for CTL anti-tumor activity. Furthermore, PL120131 can maintain co-culture survivability and activity of T Cells in a 3D co-culture model better than the anti-PD-1 blocking antibody. Together, the characterization of this PD-1/PD-L1 inhibiting peptide provides insight regarding the ability to inhibit PD-L1 binding while maintaining CTL viability and activity that can further the development of alternatives to antibody...
PD-1, PD-L1 mechanism and cancer treatment
2021
In response to a foreign organism or material, our bodies react with a variety of immunological agents. This response mechanism is called immunogenicity. While some of the proteins that regulate the immune response function to activate this response, some of them are responsible for inhibiting this response. The main "brake" proteins involved in this negative regulation are cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein-1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein-3, and lymphocyte-activation gene-3. The cell can differentiate endogenous and exogenous substances through these brakes and other signal pathways. In the presence of brake proteins, the tumor cells are not perceived as a threat by the immune system, so a corresponding response does not occur. To generate this response, drugs containing monoclonal antibodies are produced for use in cancer treatments. Monoclonal antibodies are designed to block braking processes while also eliciting an immunological response. In this review, the PD-1 and programmed cell death-ligand 1 pathway and cancer immunotherapy are mentioned.
ImmunoHorizons, 2023
Seven different anti-PD-1 and PD-L1 mAbs are now widely used in the United States to treat a variety of cancer types, but no clinical trials have compared them directly. Furthermore, because many of these Abs do not cross-react between mouse and human proteins, no preclinical models exist in which to consider these types of questions. Thus, we produced humanized PD-1 and PD-L1 mice in which the extracellular domains of both mouse PD-1 and PD-L1 were replaced with the corresponding human sequences. Using this new model, we sought to compare the strength of the immune response generated by Food and Drug Administration-approved Abs. To do this, we performed an in vivo T cell priming assay in which anti-PD-1/L1 therapies were given at the time of T cell priming against surrogate tumor Ag (OVA), followed by subsequent B16-OVA tumor challenge. Surprisingly, both control and Ab-treated mice formed an equally robust OVA-specific T cell response at the time of priming. Despite this, anti-PD-1/L1-treated mice exhibited significantly better tumor rejection versus controls, with avelumab generating the best protection. To determine what could be mediating this, we identified the increased production of CX3CR1 + PD-1 + CD8 + cytotoxic T cells in the avelumab-treated mice, the same phenotype of effector T cells known to increase in clinical responders to PD-1/L1 therapy. Thus, our model permits the direct comparison of Food and Drug Administration-approved anti-PD-1/L1 mAbs and further correlates successful tumor rejection with the level of CX3CR1 + PD-1 + CD8 + T cells, making this model a critical tool for optimizing and better utilizing anti-PD-1/L1 therapeutics. ImmunoHorizons, 2023, 7: 125-139.
Cancers
Antibodies targeting Immune Checkpoints (IC) on tumor infiltrating lymphocytes improve immune responses against cancer. Recently, the expression of some ICs has also been reported on cancer cells. We used the clinically validated Ipilimumab and Nivolumab and other novel human antibodies targeting Cytotoxic T- lymphocyte-antigen 4 (CTLA-4), Programmed Death receptor-1 (PD-1) and Programmed Death Ligand 1 (PD-L1) to shed light on the functions of these ICs in cancer cells. We show here for the first time that all these antagonistic mAbs are able to reduce Erk phosphorylation and, unexpectedly, to induce a significant increase of ICs expression on tumor cells, involving a hyperphosphorylation of NF-kB. On the contrary, agonistic PD-L1 and PD-1 recombinant proteins showed opposite effects by leading to a significant reduction of PD-1 and PD-L1, thus also suggesting the existence of a crosstalk in tumor cells between multiple ICs. Since the immunomodulatory mAbs show their higher anti-tu...