A novel human single-domain antibody-drug conjugate targeting CEACAM5 exhibits potent in vitro and in vivo antitumor activity  

作　　者：Xiao-yi Zhu Quan-xiao Li Yu Kong Ke-ke Huang Gang Wang Yun-ji Wang Jun Lu Guo-qiang Hua Yan-ling Wu Tian-lei Ying 

机构地区：[1]MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology,Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai 200032,China [2]Shanghai Engineering Research Center for Synthetic Immunology,Shanghai 200032,China [3]Auckland Bioengineering Institute,University of Auckland,Auckland 1010,New Zealand [4]Cancer Institute,Fudan University Shanghai Cancer Center,Shanghai 200032,China

出　　处：《Acta Pharmacologica Sinica》2024年第3期609-618,共10页中国药理学报（英文版）

基　　金：supported by National Key R&D Program of China(2019YFA0904400);National Natural Science Foundation of China(32270984).

摘　　要：Leveraging the specificity of antibody to deliver cytotoxic agent into tumor,antibody-drug conjugates(ADCs)have become one of the hotspots in the development of anticancer therapies.Although significant progress has been achieved,there remain challenges to overcome,including limited penetration into solid tumors and potential immunogenicity.Fully human single-domain antibodies(UdAbs),with their small size and human nature,represent a promising approach for addressing these challenges.Carcinoembryonic antigen-related cell adhesion molecule 5(CEACAM5)is a glycosylated cell surface protein that rarely expressed in normal adult tissues but overexpressed in diverse cancers,taking part in tumorigenesis,progression,and metastasis.In this study,we investigated the therapeutic potential of UdADC targeting CEACAM5.We performed biopanning in our library and obtained an antibody candidate B9,which bound potently and specifically to CEACAM5 protein(K_(D)=4.84 nM)and possessed excellent biophysical properties(low aggregation tendency,high homogeneity,and thermal stability).The conjugation of B9 with a potent cytotoxic agent,monomethyl auristatin E(MMAE),exhibited superior antitumor efficacy against CEACAM5-expressing human gastric cancer cell line MKN-45,human pancreatic carcinoma cell line BxPC-3 and human colorectal cancer cell line LS174T with IC_(50) values of 38.14,25.60,and 101.4 nM,respectively.In BxPC-3 and MKN-45 xenograft mice,administration of UdADC B9-MMAE(5 mg/kg,i.v.)every 2 days for 4 times markedly inhibited the tumor growth without significant change in body weight.This study may have significant implications for the design of next-generation ADCs.

关 键 词：solid tumors antibody-drug conjugate CEACAM5 single-domain antibody monomethyl auristatin E 

分 类 号：R73[医药卫生—肿瘤]