Abstract:Cancer cells express tumour-specific antigens derived via genetic and epigenetic alterations, which may be targeted by T-cell-mediated immune responses. However, cancer cells can avoid immune surveillance by suppressing immunity through activation of specific inhibitory signalling pathways, referred to as immune checkpoints. In recent years, the blockade of checkpoint molecules such as PD-1, PD-L1 and CTLA-4, with monoclonal antibodies has enabled the development of breakthrough therapies in oncology, and four… Show more
“…This is consistent with the general observation that the LCDR2 of antibodies is often not involved in antigen binding. The previously reported structures of PD-L1 in complex with BMS-963559 or avelumab demonstrated that these two antibodies similary involved only five of the six CDRs in the interaction with PD-L1, leaving LCDR2 without any binding to PD-L1 38, 39 .Figure 1Crystal structures of PD-1 in complex with atezolizumab and durvalumab. ( a ) Ribbon representation of the complex structure of PD-L1/atezolizumab Fab fragment.…”
Section: Resultsmentioning
confidence: 95%
“…Recently, the crystal structures of PD-L1 in complex with the Fab fragment of BMS-936559 and the single-chain Fv fragment (scFv) of avelumab have been determined, revealing details of the antigen-antibody interactions 38, 39 . However, the epitopes and the PD-L1 blocking mechanism of atezolizumab and durvalumab remain unclear.…”
In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.
“…This is consistent with the general observation that the LCDR2 of antibodies is often not involved in antigen binding. The previously reported structures of PD-L1 in complex with BMS-963559 or avelumab demonstrated that these two antibodies similary involved only five of the six CDRs in the interaction with PD-L1, leaving LCDR2 without any binding to PD-L1 38, 39 .Figure 1Crystal structures of PD-1 in complex with atezolizumab and durvalumab. ( a ) Ribbon representation of the complex structure of PD-L1/atezolizumab Fab fragment.…”
Section: Resultsmentioning
confidence: 95%
“…Recently, the crystal structures of PD-L1 in complex with the Fab fragment of BMS-936559 and the single-chain Fv fragment (scFv) of avelumab have been determined, revealing details of the antigen-antibody interactions 38, 39 . However, the epitopes and the PD-L1 blocking mechanism of atezolizumab and durvalumab remain unclear.…”
In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.
“…[18] The binding surfaces of peptides -57 and -71 within PD-L1 overlap partially with the epitopes of anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, and BMS-936559 (Supporting Information, Figure S15)). [19,20] Analysis of the interactions of the residues of the antibodies avelumab and BMS-936559 and the peptides shows that several residues of the peptides and the antibodies interact similarly. A number of the residues of peptide-71 mimic the amino acids of the VH domain of avelumab responsible for the interactions with PD-L1 (Supporting Information, Figures S16 and S17): for example, the hydrophobic side chains of peptide-71: 71 Phe1, 71 NMeNle3 and 71 NMePhe7, interact similarly to A Ile33, A Pro53 and A Ile57, respectively (subscript A indicates the avelumab residues).…”
Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway.
“…Moreover, a comparison of the crystal structure of the PD-1/nivolumab Fab complex (PDB ID: 5GGR) with that of PD-1/pembrolizumab (PDB ID: 5GGS) [29] indicated that the epitopes of both antibodies directly occupy part of the PD-L1 binding site and can thus outcompete PD-L1 for binding to PD-1.…”
Section: Cocrystal Structures With Monoclonal Antibodiesmentioning
The PD-1/PD-L1 interaction has emerged as a significant target in cancer immunotherapy. Current medications include monoclonal antibodies, which have shown impressive clinical results in the treatment of several types of tumors. The cocrystal structure of human PD-1 and PD-L1 is expected to be a valuable starting point for the design of novel inhibitors, along with the recent crystal structures with monoclonal antibodies, small molecules, and macrocycles.
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