,Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab

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Dear Editor, Blockade of PD-1/PD-L1 signaling pathway by monoclonal antibodies (MAbs) to release the anti-tumor activity of preexisting tumor specific Tcell immunity has initiated a new era for tumor immunotherapy. Administration of anti-PD-1 MAbs (nivolumab and pembrolizumab) in either monotherapy or in combination with anti-CTLA-4 MAbs or traditional chemotherapy has achieved a tumor regression rate of 30%-50% in dealing with melanoma, non-small cell lung cancer, etc. (Larkin et al., 2015). The approval of anti-PD-L1 atezolizumab and avelumab by US Food and Drug Administration (FDA) since 2016 has provided additional choices in dealing with multiple tumors aside from anti-PD-1 and anti-CTLA-4 MAbs as immunotherapeutic medication. The structures of the two therapeutic anti-PD-1 MAbs, nivolumab and pembrolizumab, complexed with PD-1 have been reported which elucidated the molecular basis of MAb-based anti-PD-1 immunotherapy (Tan et al., 2016a, b; Na et al., 2017; Tan et al., 2017). Complex structures of avelumab and BMS-936559 with PD-L1 were also reported which contributes a better understanding of the molecular basis of MAb-based anti-PD-L1 checkpoint blockade therapy (Lee et al., 2016; Liu et al., 2017). In addition, two additional anti-PD-L1 MAbs are in clinics or phase III trials, atezolizumab and durvalumab. Durvalumab (MEDI4736) is a fully human lgG1 MAb targeting PD-L1 that was deveh oped by AstraZeneca, and has been approved by US FDA very recently. Multiple Phase III clinical trials are still ongoing in non-small cell lung cancer, head and neck cancer, urothelial cancer, etc. (NCT02542293, NCT02369874, NCT02516241, etc. ). A Phase lb report demonstrated that durvalumab is well tolerated and showed promising anti-tumor efficacy in non-small cell lung cancer patients (Antonia et al., 2016). However, the molecular basis of durvalumab-based anti-PD-L1 reactivity and binding characteristics compared to the other three MAbs used in clinics has not yet been elucidated.
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