Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab

Lee, Hyun Tae; Lee, Ju‐Yeon; Lim, Heejin; Lee, Sang Hyung; Moon, Yu Jeong; Pyo, Hyo Jeong; Ryu, Seong Eon; Shin, Woo‐Ri; Heo, Yong Seok

doi:10.1038/s41598-017-06002-8

Cited by 179 publications

(154 citation statements)

References 54 publications

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“…Several crystal structures of the anti‐PD‐1 and anti‐PD‐L1 monoclonal antibodies have been published and illustrate the structural basis of PD‐1 and PD‐L1 blockade by the antibodies. A thorough understanding of the epitopes of these therapeutic antibodies will be instructive in the identification of key amino acid residues to target in the design of small molecule inhibitors of this immune checkpoint.…”

Section: Antibody‐based Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…In general, all the anti‐PD‐L1 antibodies compete with PD‐1 for the same surface area on PD‐L1 to block the PD‐1/PD‐L1 interaction. Interestingly, the binding of the three anti‐PD‐L1 antibodies and PD‐1 all involve the Tyr56, Glu58, Arg113, Met115, and Tyr123 residues on PD‐L1 . These amino acids may be pivotal in the design of small molecule inhibitors of the PD‐1/PD‐L1 protein‐protein interaction (PPI).…”

Section: Antibody‐based Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

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Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

145

121

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Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.

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Section: Antibody‐based Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Antibody‐based Pd‐1/pd‐l1 Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Yang

2018

Medicinal Research Reviews

145

121

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“…Phase 2 trials with nivolumab in patients with DLBCL (CHECKMATE 139, NCT02038933) have mature results. No response was observed in a cohort of MCL patients who receive nivolumab (78).…”

Section: Immune Checkpoint Inhibitors (Icis)mentioning

confidence: 96%

Overview of Targeted Drugs for Mature B-Cell Non-hodgkin Lymphomas

et al. 2019

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The improved knowledge of pathogenetic mechanisms underlying lymphomagenesis and the discovery of the critical role of tumor microenvironments have enabled the design of new drugs against cell targets and pathways. The Food and Drug Administration (FDA) has approved several monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) for targeted therapy in hematology. This review focuses on the efficacy results of the currently available targeted agents and recaps the main ongoing trials in the setting of mature B-Cell non-Hodgkin lymphomas. The objective is to summarize the different classes of novel agents approved for mature B-cell lymphomas, to describe in synoptic tables the results they achieved and, finally, to draw future scenarios as we glimpse through the ongoing clinical trials. Characteristics and therapeutic efficacy are summarized for the currently approved mAbs [i.e., anti-Cluster of differentiation (CD) mAbs, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and bispecific antibodies] as well as for SMIs i.e., inhibitors of B-cell receptor signaling, proteasome, mTOR BCL-2 HDAC pathways. The biological disease profiling of B-cell lymphoma subtypes may foster the discovery of innovative drug strategies for improving survival outcome in lymphoid neoplasms, as well as the trade-offs between efficacy and toxicity. The hope for clinical advantages should carefully be coupled with mindful awareness of the potential pitfalls and the occurrence of uneven, sometimes severe, toxicities.

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“…The heavy chain and light chain regions of these antibodies are involved in binding, with varying buried surface areas on each molecule which may affect their binding affinities [42,43]. These three antibodies have been noted to use all three complementarity determining regions from their heavy chains and two from the light chains [43,44].…”

Section: Anti-pd-1/pd-l1mentioning

confidence: 99%

Structure and Optimization of Checkpoint Inhibitors

Picardo

Doi

Hansen

2019

Cancers

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With the advent of checkpoint inhibitor treatment for various cancer types, the optimization of drug selection, pharmacokinetics and biomarker assays is an urgent and as yet unresolved dilemma for clinicians, pharmaceutical companies and researchers. Drugs which inhibit cytotoxic T-lymphocyte associated protein-4 (CTLA-4), such as ipilimumab and tremelimumab, programmed cell death protein-1 (PD-1), such as nivolumab and pembrolizumab, and programmed cell death ligand-1 (PD-L1), such as atezolizumab, durvalumab and avelumab, each appear to have varying pharmacokinetics and clinical activity in different cancer types. Each drug differs in terms of dosing, which becomes an issue when drug comparisons are attempted. Here, we examine the various checkpoint inhibitors currently used and in development. We discuss the antibodies and their protein targets, their pharmacokinetics as measured in various tumor types, and their binding affinities to their respective antigens. We also examine the various dosing regimens for these drugs and how they differ. Finally, we examine new developments and methods to optimize delivery and efficacy in the field of checkpoint inhibitors, including non-fucosylation, prodrug formations, bispecific antibodies, and newer small molecule and peptide checkpoint inhibitors.

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Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab

Cited by 179 publications

References 54 publications

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

Overview of Targeted Drugs for Mature B-Cell Non-hodgkin Lymphomas

Structure and Optimization of Checkpoint Inhibitors

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