T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin  

作　　者：Jun-jun Liu Zhi-di Pan Ya-li Yue Shu-sheng Wang Jie Chen Hua Jiang Bao-hong Zhang Ming-yuan Wu Yun-sheng Yuan Yan-lin Bian Hai-yang Yin Lei Wang Jun-yan Li John Gilly Yue-qing Xie Jian-wei Zhu 

机构地区：[1]Engineering Research Center of Cell and Therapeutic Antibody,Ministry of Education,School of Pharmacy,Shanghai Jiao Tong University,Shanghai,200240,China [2]Jecho Institute,Shanghai,200240,China [3]Jecho Laboratories,Inc.,Frederick,MD,21704,USA [4]Jecho Biopharmaceuticals Co.,Ltd,Tianjin,300450,China

出　　处：《Acta Pharmacologica Sinica》2024年第10期2186-2198,共13页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant No.81773621 and 82073751 to JWZ);the National Science and Technology Major Project“Key New Drug Creation and Manufacturing Program”of China(Grant No.2019ZX09732001-019 to JWZ).

摘　　要：T cell engaging bispecific antibodies(TCBs)have recently become significant in cancer treatment.In this study we developed MSLN490,a novel TCB designed to target mesothelin(MSLN),a glycosylphosphatidylinositol(GPI)-linked glycoprotein highly expressed in various cancers,and evaluated its efficacy against solid tumors.CDR walking and phage display techniques were used to improve affinity of the parental antibody M912,resulting in a pool of antibodies with different affinities to MSLN.From this pool,various bispecific antibodies(BsAbs)were assembled.Notably,MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors(EC_(50):0.16 pM in HT-29-hMSLN cells).Furthermore,MSLN490 remained effective even in the presence of non-membrane-anchored MSLN(soluble MSLN).Moreover,the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA×CD28 BsAbs.Notably,a synergistic effect was observed between MSLN490 and paclitaxel,as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors,enhancing immune cells infiltration and improved anti-tumor efficacy.Overall,MSLN490 exhibits robust anti-tumor activity,resilience to soluble MSLN interference,and enhanced anti-tumor effects when combined with other therapies,offering a promising future for the treatment of a variety of solid tumors.This study provides a strong foundation for further exploration of MSLN490’s clinical potential.

关 键 词：solid tumors T cell engaging bispecific antibodies MSLN490 MESOTHELIN PACLITAXEL 

分 类 号：R73[医药卫生—肿瘤]