| 1 | Rational development of a human antibody cocktail that deploys multiple functions to confer Pan-SARS-CoVs protection显示文摘Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined.Here,we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2.On the basis of our previously identified humanized cross-neutralizing antibody H014,we systematically an a lyzed a fully human n aive antibody library and rationally identified a potent neutralizing antibody partner,P17,which confers effective protection in animal model.Cryo-EM studies dissected the nature of the P17 epitope,which is SARS-CoV-2 specific and distinctly different from that of HOI4.High-resolution structure of the SARS-CoV-2 spike in complex with HOM and P17,together with functional investigations revealed that in a two-antibody cocktail,synergistic neutralization was achieved by S1 shielding and conformational locking,thereby blocking receptor attachment and viral membrane fusion,conferring high potency as well as robustness against viral mutation escape.Furthermore,cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics. | Hangping Yao Yao Sun Yong-Qiang Deng Nan Wang Yongcong Tan Na-Na Zhang Xiao-Feng Li Chao Kong Yan-Peng Xuc Qi Chen Tian-Shu Cao Hui Zhao Xintian Yan Lei Cao Zhe Lv Dandan Zhu Rui Feng Nanping Wu Wenhai Zhang Yuhao Hu Keda Chen Rong-Rong Zhang Qingyu Lv Shihui Sun Yunhua Zhou Run Yan Guan Yang Xinglu Chanjuan Liu Xiangyun Lu Linfang Cheng Hongying Qiu Xing-Yao Huang Tianhao Weng Danrong Shi Weidong Jiang Junbin Shao Lei Wang Jie Zhang Tao Jiang Guojun Lang Cheng-Feng Qinc Lanjuan Li Xiangxi Wang | 2021 | Cell Research2021，31，1： | 5 |
| 4 | Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial显示文摘Anaplastic lymphoma kinase(ALK)rearrangements are present in about 5–6%of non-small cell lung cancer(NSCLC)cases and associated with increased risks of central nervous system(CNS)involvement.Envonalkib,a novel ALK inhibitor,demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study.This phase III trial(ClinicalTrials.gov NCT04009317)investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases.Totally 264 participants were randomized 1:1 to receive envonalkib(n=131)or crizotinib(n=133).Median independent review committee(IRC)-assessed progression-free survival(PFS)times were 24.87(95%confidence interval[CI]:15.64–30.36)and 11.60(95%CI:8.28–13.73)months in the envonalkib and crizotinib groups,respectively(hazard ratio[HR]=0.47,95%CI:0.34–0.64,p<0.0001).IRC-assessed confirmed objective response rate(ORR)was higher(81.68%vs.70.68%,p=0.056)and duration of response was longer(median,25.79[95%CI,16.53–29.47]vs.11.14[95%CI,9.23–16.59]months,p=0.0003)in the envonalkib group compared with the crizotinib group.In participants with baseline brain target lesions,IRC-assessed CNS-ORR was improved with envonalkib compared with crizotinib(78.95%vs.23.81%).Overall survival(OS)data were immature,and median OS was not reached in either group(HR=0.84,95%CI:0.48–1.47,p=0.5741).The 12-month OS rates were 90.6%(95%CI,84.0%–94.5%)and 89.4%(95%CI,82.8%–93.6%)in the envonalkib and crizotinib groups,respectively.Grade≥3 treatment-related adverse events were observed in 55.73%and 42.86%of participants in the envonalkib and crizotinib groups,respectively.Envonalkib significantly improved PFS and delayed brain metastasis progression in advanced ALK-positive NSCLC. | Yunpeng Yang Jie Min Nong Yang Qitao Yu Ying Cheng Yanqiu Zhao Manxiang Li Hong Chen Shou’an Ren Jianying Zhou Wu Zhuang Xintian Qin Lejie Cao Yan Yu Jian Zhang Jianxing He Jifeng Feng Hao Yu Li Zhang Wenfeng Fang | 2023 | Signal Transduction and Targeted Therapy2023，8，9： | 0 |
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