W101 elucidate trial#

A clinical trial of a combination therapy involving durvalumab and an anti-CTLA-4 antibody, tremelimumab, showed antitumor activity in NSCLC regardless of PD-L1 status, suggesting that this combination has therapeutic potential for patients with PD-L1-negative tumors 31. Among these, the combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies has been the most successful, probably because PD-1/PD-L1 and CTLA-4/B7 interactions play different roles in T-cell immunity 6, 28, 29, 30. In addition, other anti-PD-L1 antibodies including BMS-936559 are in multiple clinical trials for the treatment of NSCLC, renal cell cancer, head and neck cancer, gastric cancer, and other cancers 24, 25, 26, 27.Д¬ombinations of anti-PD-1/PD-L1 antibodies with other therapies are being explored as potentially synergistic therapeutic strategies. Prior to the approval of the anti-PD-L1 antibodies, the anti-PD-1 drugs pembrolizumab (KeytrudaВ®) and nivolumab (OpdivoВ®) have been widely used clinically and demonstrated unprecedented therapeutic benefits since 2014 19, 20, 21, 22, 23. In 2017, avelumab (BavencioВ®) and durvalumab (ImfinziВ®) were also approved by the FDA for Merkel-cell carcinoma and advanced bladder cancer, respectively (Supplementary Table S1). The FDA approved the first anti-PD-L1 drug, atezolizumab (TecentriqВ®), for the treatment of advanced urothelial carcinoma in May 2016 and metastatic non-small cell lung cancer (NSCLC) in October 2016 15, 16, 17, 18. The success of antibody-based PD-1/PD-L1 blockade therapies has provided a major breakthrough in the fight against human cancers, especially for solid tumors. Thus, blocking the PD-1/PD-L1 interaction can restore T-cell activation and antitumor responses 12, 13, 14. PD-L1 is often overexpressed in different tumors, and its interaction with PD-1 on T cells enables cancer cells to evade T-cell-mediated immune responses 11. As a result, PD-1 signaling prevents excessive or harmful inflammation and maintains immune tolerance to self-antigens under normal conditions 10. Ligation of PD-1 with its two ligands initiates co-inhibitory signaling through the cytoplasmic domain of PD-1, containing an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, thus leading to activation of SHP phosphatases that downregulate TCR signaling by dephosphorylating effector molecules involved in the signaling 8, 9. PD-L1 and PD-L2 are commonly expressed on dendritic cells and macrophages, and their ectodomains are composed of a membrane distal IgSF V-set and a membrane proximal IgSF C-set domains 6, 7. PD-1 is a type I membrane protein with a single extracellular immunoglobulin superfamily (IgSF) V-set domain that is expressed on the surface of activated T cells in peripheral tissues 4, 5.

Programmed death 1 (PD-1) and its ligands PD-L1 and PD-L2 are key co-inhibitory molecules in the modulation of T-cell mediated immune responses 1, 2, 3. 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. 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. 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. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. And many other anti-PD-L1 antibodies are under clinical trials. In 20, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers.

W101 elucidate