The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.However,several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight,and thus its clinical use is limited.Furthermore,multiple trials have shown that approximately 30％of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells.Here,we design and characterize two novel antibodies,A-319 and A-2019.Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures,and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function.Our in vitro,ex vivo,and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells,enhancing T-cell function,mediating B-cell depletion,and eventually inhibiting tumor growth in Raji xenograft models.The two molecules are complementary in terms of efficacy and specificity profile.The activity of A-319 demonstrated superior to that of A-2019,whereas A-2019 has an additional capability to target CD20 in cells missing CD19,suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

Sisi Wang;Lijun Peng;Wenqian Xu;Yuebo Zhou;Ziyan Zhu;Yushan Kong;Stewart Leung;Jin Wang;Xiaoqiang Yan;Jian-Qing Mi

Shanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Center for Translational Medicine at Shanghai,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;P?le Franco-Chinois de Recherche en Sciences du Vivant et Genomique,Shanghai 200025,China;Shanghai Blood Center,Shanghai 200051,China;Generon Biomed,Shanghai 201210,China

医学前沿

[1]Sisi Wang;Lijun Peng;Wenqian Xu;Yuebo Zhou;Ziyan Zhu;Yushan Kong;Stewart Leung;Jin Wang;Xiaoqiang Yan;Jian-Qing Mi-.Preclinical characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cell acute lymphoblastic leukemia:targeted immunotherapy for acute lymphoblastic leukemia)[J].医学前沿,2022(01):139-149

trispecific,engager,Blinatumomab

Preclinical,characterization,comparison,between,CD3,CD19,bispecific,novel,CD20,antibodies,against,acute,lymphoblastic,leukemia,targeted,immunotherapy,targeting,blinatumomab,has,shown,remarkable,efficacy,patients,relapsed,refractory,precursor,However,several,studies,showed,that,short,plasma,half,life,due,its,low,molecular,weight,thus,use,limited,Furthermore,multiple,trials,have,approximately,cases,are,characterized,by,negative,leukemic,cells,Here,design,two,different,sizes,structures,antibody,additional,function,Our,vitro,vivo,experiments,demonstrated,antitumor,agents,capable,recruiting,positive,enhancing,mediating,depletion,eventually,inhibiting,growth,Raji,xenograft,models,molecules,complementary,terms,specificity,profile,activity,superior,whereas,capability,missing,suggesting,potential,weak

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