A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018)

Shaabani, Shabnam; Huizinga, Harmen P.S.; Butera, Roberto; Kouchi, Ariana; Guzik, Krzysztof; Magiera‐Mularz, Katarzyna; Holak, Tad A.; Dömling, Alexander

doi:10.1080/13543776.2018.1512706

Cited by 123 publications

(94 citation statements)

References 6 publications

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“…The rapid development of tumor immunotherapy and the promising clinical More and more research institutions and enterprises have accelerated the protection of biomarker products in the field of intellectual property. These patents are mainly the methods of tumor diagnosis or prognosis by biomarkers, including the new biomarkers discovery, new or improved diagnostic methods, etc [58][59][60][61][62] . The research results of biomarkers for diagnosis and treatment can directly guide the development of diagnostic tools and the selection of therapeutic drugs, which have great market prospects.…”

Section: Technological Development Focusmentioning

confidence: 99%

The development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics

Zhang

2020

Preprint

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Background: This paper aims to show the scientific research and technological development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics. Methodology/Principal Findings: Publications and patents related to antineoplastics targeting PD-1/PD-L1were searched and collected from the Web of Science (WoS) and the Derwent Innovation Index (DII) respectively. Totally, 11244 publications and 5501 patents were obtained. The publications were analyzed from the annual number, the top countries/regions and organizations to describe the scientific research trends in this field. The patents were analyzed from the annual number, the top priority countries and patent assignees to reveal the characteristics and status of technological development. As well as the identification of scientific research focus and technological development focus was based on the title and abstract of the publications and patents, using the freely available computer program VOSviewer for clustering and visualization analysis.The number of scientific publications and patent applications showed obvious increase of 29.84% and 33.46% in recent ten years (2009-2018), respectively. Results suggested that the most productive countries/regions publishing on antineoplastics targeting PD-1/PD-L1 were USA and China, and the top three productive organizations were all from USA, including Harvard University, VA Boston Healthcare System (VA BHS) and University Of California System. There were four scientific research focus: (1) immune escape mechanism, (2) biomarkers related to efficacy and prognosis, (3) immune-related adverse event, and (4) drug design and preparation, and five technological development focus: (1) testing methods and apparatus, (2) indications related to carcinoma, (3) biomarkers related to diagnosis and prognosis, (4) small molecule inhibitors, and (5) indications other than carcinoma. Conclusions/Significance:The results of this study presents an overview of the characteristics of research status and trends of antineoplastics targeting PD-1/PD-L1, which could help readers broaden innovative ideas and discover new technological opportunities, and also serve as important indicators for government policymaking.

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Section: Technological Development Focusmentioning

confidence: 99%

The development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics

Zhang

2020

Preprint

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“…antagonists, small molecule PD-L1 dimerizer and small molecules whose mode-of-action remains unknown [25], but most of them have only modest inhibitory activity [26].…”

Section: Other Moleculesmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Melanoma: A Review of Pharmacokinetics and Exposure–Response Relationships

et al. 2019

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Immune checkpoint inhibitors are a new class of monoclonal antibodies that amplify T-cell-mediated immune responses against cancer cells. The introduction of these new drugs, first anti-CTLA4 and then anti-PD1, was a major advance in the treatment of advanced or metastatic melanoma, a highly immunogenic tumor. The development strategy for immune checkpoint immunotherapies differed from that traditionally used for cytotoxic therapies in oncology. The choices of doses at which to conduct clinical trials and subsequently the choices of doses at which to use these new therapies were not based on the identification of a maximum tolerated dose from dose escalation studies. Thus, pharmacokinetic and pharmacokinetic-pharmacodynamic modelling was essential. The studies conducted have shown that the pharmacokinetics of ipilimumab was linear and not time-dependent. In addition, there was a correlation between the trough concentrations of ipilimumab and its therapeutic efficacy. On the contrary, the anti-PD1 immunotherapies nivolumab and pembrolizumab had a time-dependent pharmacokinetics. Their therapeutic efficacy was not related to their trough concentration, but there was a correlation between the clearance of anti-PD1 and the survival of melanoma patients. This review highlights the complexity of interpreting the exposure-response relationships of these agents. Further studies will be needed to assess the value of therapeutic drug monitoring of immune checkpoint inhibitors in the treatment of melanoma. Key Points  Immune checkpoint inhibitors are a new class of anti-cancer drugs; the characterization of their exposure-response relationships is still ongoing.  The steady state minimum concentrations of anti-CTLA4 ipilimumab are correlated with its therapeutic efficacy, but a range of optimal concentrations to maximize therapeutic efficacy and tolerability has not yet been identified. A c c e p t e d m a n u s c r i p t 3  No correlation was found between exposure to the anti-PD1 pembrolizumab and nivolumab and their therapeutic efficacy and tolerability for the doses studied in the clinical trials. However, the clearances of anti-PD1 are correlated with the survival rates of melanoma patients.

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“…According to that study, BTLA binds with HVEM on two fragments: BTLA (amino acids [35][36][37][38][39][40][41][42][43] and BTLA (amino acids 118-128), which interact with the CRD1 domain of HVEM. The fragment HVEM (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) was shown to be directly involved in the binding of BTLA, and the N-terminal part of CRD1 does not participate in the formation of the protein complex [20]. The crystal structure of BTLA/HVEM shows that the interaction between both proteins is primarily stabilized by hydrogen bonds of the main chain and that there are few side-chain interactions [23].…”

Section: Introductionmentioning

confidence: 99%

“…In earlier years, researchers focused on the screening of small molecules as inhibitors of protein-protein interactions (PPIs) [1,[25][26][27]. More recently, peptides have shown great potential as alternatives for inhibiting PPIs [28].…”

Section: Introductionmentioning

confidence: 99%

Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding

Spodzieja

Kuncewicz

Sieradzan

et al. 2020

IJMS

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Immune checkpoints are crucial in the maintenance of antitumor immune responses. The activation or blockade of immune checkpoints is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals, including the enhancement or suppression of T-cell proliferation, differentiation, and/or cytokine secretion. B-and T-lymphocyte attenuator (BTLA) is a lymphoid-specific cell surface receptor which is present on T-cells and interacts with herpes virus entry mediator (HVEM), which is present on tumor cells. The binding of HVEM to BTLA triggers an inhibitory signal which attenuates the immune response. This feature is interesting for studying the molecular interactions between HVEM and BTLA, as they may be targeted for novel immunotherapies. This work was based on the crystal structure of the BTLA/HVEM complex showing that BTLA binds the N-terminal cysteine-rich domain of HVEM. We investigated the amino acid sequence of HVEM and used molecular modeling methods to develop inhibitors of the BTLA/HVEM interaction. We synthesized novel compounds and determined their ability to interact with the BTLA protein and inhibit the formation of the BTLA/HVEM complex. Our results suggest that the HVEM (14–39) peptide is a potent inhibitor of the formation of the BTLA/HVEM protein complex.

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A patent review on PD-1/PD-L1 antagonists: small molecules, peptides, and macrocycles (2015-2018)

Cited by 123 publications

References 6 publications

The development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics

The development trends of antineoplastics targeting PD-1/PD-L1 based on scientometrics and patentometrics

Immune Checkpoint Inhibitors in Melanoma: A Review of Pharmacokinetics and Exposure–Response Relationships

Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding

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