Inhibitors of programmed cell death 1 (PD-1): a patent review (2010-2015)

Zarganes‐Tzitzikas, Tryfon; Konstantinidou, Markella; Gao, Yongzhi; Krzemień, Dobrosława; Żak, Krzysztof; Dubin, Grzegorz; Holak, Tad A.; Dömling, Alexander

doi:10.1080/13543776.2016.1206527

Cited by 88 publications

(75 citation statements)

References 11 publications

(11 reference statements)

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“…In the tumor microenvironment, the activated PD-1/B7-H1 (programmed cell death 1/ PD-L1) signaling pathway makes T lymphocytes functionally inactivated [2,5], which decreases the anti-tumor activity of T cells. So far, the PD-1 antibodies (pembrolizumab and PLOS ONE PLOS ONE | https://doi.org/10.1371/journal.pone.0228339 March 26, 2020 1 / 15 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 nivolumab), have been approved for the treatment of the advanced melanoma [2,6,7].…”

Section: Introductionmentioning

confidence: 99%

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

et al. 2020

PLoS ONE

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The increased PD-L1 expression induces poorer prognosis in melanoma. The small molecule inhibitors of PD-1/PD-L1 pathways have been an encouraging drug development strategy because of good affinity and oral bioavailability without immunogenicity and immunotoxicities of PD-1/PD-L1 antibodies. In this study, we studied the effects of PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, on PD-1/PD-L1 binding and the cytokines secretion in human CD3 + cells in vitro. We also investigated the antitumor and immunomodulatory activity of PCC0208025 and the pharmacokinetics properties in B16-F10 melanoma-bearing mice. The results showed that PCC0208025 inhibited the PD-1/PD-L1 proteins binding, and rescued PD-L1-mediated inhibition of IFN-γ production in human CD3 + T cells in vitro. Furthermore, in B16-F10 melanoma-bearing mice, PCC0208025 presented the antitumor effects, enhanced IFN-γ levels in plasma, increased the frequency of CD3 + CD8 + T and CD8 + IFN-γ + T and the ratios of CD8 + /Treg, and deceased the CD4 + CD25 + CD127 low/− (Treg) number in tumor. Pharmacokinetics study found that PCC0208025 was absorbed and distributed into the tumors with much higher concentrations than those of the blockade against PD-1/PD-L1 binding. Our work suggests that PCC0208025 exhibited anti-tumor effects through inhibiting Treg expansion and increasing cytotoxic activity of tumor-infiltrating CD8 + T cells by the blockade of PD-1/PD-L1 binding, which may provide the pharmacological basis to develop small molecule inhibitors of PD-1/PD-L1 binding for PCC0208025 as a lead compound.

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Section: Introductionmentioning

confidence: 99%

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

et al. 2020

PLoS ONE

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“…However, therapeutic antibodies exhibit several disadvantages, such as limited tissue and tumor penetration, very long half‐life time, immunogenicity, and costly production. Moreover, the current PD‐1/PD‐L1 axis‐directed monoclonal antibodies lead to a tumor response only in a fraction of cases and tumor types . Therefore, the application of alternative, nonantibody‐based agents to inhibit PD‐1/PD‐L1 axis is currently a new goal within the field …”

Section: Methodsmentioning

confidence: 99%

Immune Checkpoint Blockade Mediated by a Small‐Molecule Nanoinhibitor Targeting the PD‐1/PD‐L1 Pathway Synergizes with Photodynamic Therapy to Elicit Antitumor Immunity and Antimetastatic Effects on Breast Cancer

Zhang

Zhu

et al. 2019

Small

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In recent years, stimulating the host immune system to create a promising antitumor immune therapy has been demonstrated to control metastatic tumor growth. [1] Research enthusiasm has been fueled by recent clinical successes in which antibodies were used to block immune inhibitory pathways, specifically the axis between programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1). [2] However, therapeutic antibodies exhibit several disadvantages, such as limited tissue and tumor penetration, very long half-life time, immunogenicity, and costly production. Moreover, the current PD-1/PD-L1 axis-directed monoclonal antibodies lead to a tumor response only in a fraction of cases and tumor types. [3] Therefore, the application of alternative, nonantibody-based agents to inhibit PD-1/ PD-L1 axis is currently a new goal within the field. [4] The development of organic smallmole cule inhibitors is expected to introduce a number of advantages in the field of PD-1/PD-L1 immune checkpoint Targeting programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immunologic checkpoint blockade with monoclonal antibodies has achieved recent clinical success in antitumor therapy. However, therapeutic antibodies exhibit several issues such as limited tumor penetration, immunogenicity, and costly production. Here, Bristol-Myers Squibb nanoparticles (NPs) are prepared using a reprecipitation method. The NPs have advantages including passive targeting, hydrophilic and nontoxic features, and a 100% drug loading rate. BMS-202 is a small-molecule inhibitor of the PD-1/PD-L1 interaction that is developed by BMS. Transfer of BMS-202 NPs to 4T1 tumor-bearing mice results in markedly slower tumor growth to the same degree as treatment with anti-PD-L1 monoclonal antibody (α-PD-L1). Consistently, the combination of Ce6 NPs with BMS-202 NPs or α-PD-L1 in parallel shows more efficacious antitumor and antimetastatic effects, accompanied by enhanced dendritic cell maturation and infiltration of antigen-specific T cells into the tumors. Thus, inhibition rates of primary and distant tumors reach >90%. In addition, BMS-202 NPs are able to attack spreading metastatic lung tumors and offer immune-memory protection to prevent tumor relapse. These results indicate that BMS-202 NPs possess effects similar to α-PD-L1 in the therapies of 4T1 tumors. Therefore, this work reveals the possibility of replacing the antibody used in immunotherapy for tumors with BMS-202 NPs.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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“…[41] Ein Überblick über die potenziellen PD-1/PD-L1-Inhibitoren aus Patenten ist im Folgenden zusammengestellt.…”

Section: Cokristallstrukturen Mit Niedermolekularen Wirkstoffenunclassified

Der Immuncheckpoint PD‐1/PD‐L1: Gibt es Therapieoptionen jenseits der Antikörper?

Konstantinidou¹,

Zarganes‐Tzitzikas²,

Magiera‐Mularz³

et al. 2018

Angewandte Chemie

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Die PD‐1/PD‐L1‐Wechselwirkung hat sich als ein wichtiger Angriffspunkt für die Krebs‐Immuntherapie erwiesen. Aktuelle Medikationen unter Einbeziehung monoklonaler Antikörper zeigen eindrucksvolle klinische Wirkungen beim Einsatz gegen verschiedene Tumortypen. Von der Cokristallstruktur von humanem PD‐1 mit PD‐L1 erwartet man – zusammen mit den aktuellen Kristallstrukturen mit monoklonalen Antikörpern, niedermolekularen Substanzen und Makrocyclen – einen wertvollen Ausgangspunkt für den Entwurf neuer Inhibitoren.

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Inhibitors of programmed cell death 1 (PD-1): a patent review (2010-2015)

Cited by 88 publications

References 11 publications

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

PCC0208025 (BMS202), a small molecule inhibitor of PD-L1, produces an antitumor effect in B16-F10 melanoma-bearing mice

Immune Checkpoint Blockade Mediated by a Small‐Molecule Nanoinhibitor Targeting the PD‐1/PD‐L1 Pathway Synergizes with Photodynamic Therapy to Elicit Antitumor Immunity and Antimetastatic Effects on Breast Cancer

Der Immuncheckpoint PD‐1/PD‐L1: Gibt es Therapieoptionen jenseits der Antikörper?

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