A Novel Bispecific Antibody Targeting CD3 and Lewis Y with Potent Therapeutic Efficacy against Gastric Cancer

被引:20
作者
Chen, Jie [1 ]
Pan, Zhidi [1 ]
Han, Lei [2 ,3 ]
Zhou, Yuexian [1 ]
Zong, Huifang [1 ]
Wang, Lei [1 ]
Sun, Rui [1 ]
Jiang, Hua [2 ,4 ]
Xie, Yueqing [4 ]
Yuan, Yunsheng [1 ]
Wu, Mingyuan [1 ]
Bian, Yanling [1 ]
Zhang, Baohong [1 ]
Zhu, Jianwei [1 ]
机构
[1] Shanghai Jiao Tong Univ, Engn Res Ctr Cell & Therapeut Antibody, Sch Pharm, Minist Educ, Shanghai 200240, Peoples R China
[2] Jecho Biopharmaceut Co Ltd, Tianjin 300450, Peoples R China
[3] Jecho Biopharmaceut Inst, Shanghai 200240, Peoples R China
[4] Jecho Labs Inc, Frederick, MD 21704 USA
基金
中国国家自然科学基金;
关键词
Lewis Y; T cell-engaging bispecific antibody; m3s193; BsAb; cancer therapy; OVARIAN-CANCER; T-CELLS; ANTIGEN; EXPRESSION; IDENTIFICATION; PROLIFERATION; SURVIVAL; HU3S193; TUMORS; GROWTH;
D O I
10.3390/biomedicines9081059
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lewis Y antigen, a glycan highly expressed on most epithelial cancers, was targeted for cancer treatment but lacked satisfactory results in some intractable and refractory cancers. Thus, it is highly desirable to develop an effective therapy against these cancers, hopefully based on this target. In this work, we constructed a novel T cell-engaging bispecific antibody targeting Lewis Y and CD3 (m3s193 BsAb) with the IgG-[L]-scfv format. In vitro activity of m3s193 BsAb was evaluated by affinity assay to target cells, cytotoxicity assay, cytokines releasing assay, and T cells proliferation and recruiting assays. Anti-tumor activity against gastric cancer was evaluated in vivo by subcutaneous huPBMCs/tumor cells co-grafting model and huPBMCs intravenous injecting model. In vitro, m3s193 BsAb appeared to have a high binding affinity to Lewis Y positive cells and Jurkat cells. The BsAb showed stronger activity than its parent mAb in T cell recruiting, activation, proliferation, cytokine release, and cytotoxicity. In vivo, m3s193 BsAb not only demonstrated higher therapeutic efficacy in the huPBMCs/tumor co-grafting gastric carcinoma model than the parent mAb but also eliminated tumors in the model of intravenous injection with huPBMCs. Strong anti-tumor activity of m3s193 BsAb revealed that Lewis Y could be targeted in T cell-engaging BsAb for gastric cancer therapy.
引用
收藏
页数:17
相关论文
共 58 条
[31]   Expression and Correlation of Lewis y Antigen and Integrins α5 and β1 in Ovarian Serous and Mucinous Carcinoma [J].
Li, Quanrong ;
Liu, Shuice ;
Lin, Bei ;
Yan, Limei ;
Wang, Yifei ;
Wang, Changzhi ;
Zhang, Shulan .
INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, 2010, 20 (09) :1482-1489
[32]  
Lindahl U, 2015, ESSENTIALS GLYCOBIOL
[33]   Lewis(y) antigen stimulates the growth of ovarian cancer cells via regulation of the epidermal growth factor receptor pathway [J].
Liu, Juan-Juan ;
Lin, Bei ;
Hao, Ying-Ying ;
Li, Fei-Fei ;
Liu, Da-Wo ;
Qi, Yue ;
Zhu, Lian-Cheng ;
Zhang, Shu-Lan ;
Iwamori, Masao .
ONCOLOGY REPORTS, 2010, 23 (03) :833-841
[34]   Lewis y antigen promotes the proliferation of ovarian carcinoma-derived RMG-I cells through the PI3K/Akt signaling pathway [J].
Liu, Juanjuan ;
Lin, Bei ;
Hao, Yingying ;
Qi, Yue ;
Zhu, Liancheng ;
Li, Feifei ;
Liu, Dawo ;
Cong, Jianping ;
Zhang, Shulan ;
Iwamori, Masao .
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 2009, 28
[35]   MGD011, A CD19 x CD3 Dual-Affinity Retargeting Bi-specific Molecule Incorporating Extended Circulating Half-life for the Treatment of B-Cell Malignancies [J].
Liu, Liqin ;
Lam, Chia-Ying K. ;
Long, Vatana ;
Widjaja, Lusiana ;
Yang, Yinhua ;
Li, Hua ;
Jin, Linda ;
Burke, Steve ;
Gorlatov, Sergey ;
Brown, Jennifer ;
Alderson, Ralph ;
Lewis, Margaret D. ;
Nordstrom, Jeffrey L. ;
Koenig, Scott ;
Moore, Paul A. ;
Johnson, Syd ;
Bonvini, Ezio .
CLINICAL CANCER RESEARCH, 2017, 23 (06) :1506-1518
[36]   Effector-attenuating Substitutions That Maintain Antibody Stability and Reduce Toxicity in Mice [J].
Lo, Megan ;
Kim, Hok Seon ;
Tong, Raymond K. ;
Bainbridge, Travis W. ;
Vernes, Jean-Michel ;
Zhang, Yin ;
Lin, Yuwen Linda ;
Chung, Shan ;
Dennis, Mark S. ;
Zuchero, Y. Joy Yu ;
Watts, Ryan J. ;
Couch, Jessica A. ;
Meng, Y. Gloria ;
Atwal, Jasvinder K. ;
Brezski, Randall J. ;
Spiess, Christoph ;
Ernst, James A. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2017, 292 (09) :3900-3908
[37]   Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody [J].
Lopez-Albaitero, Andres ;
Xu, Hong ;
Guo, Hongfen ;
Wang, Linlin ;
Wu, Zhihao ;
Tran, Hoa ;
Chandarlapaty, Sarat ;
Scaltriti, Maurizio ;
Janjigian, Yelena ;
de Stanchina, Elisa ;
Cheung, Nai-Kong V. .
ONCOIMMUNOLOGY, 2017, 6 (03)
[38]   High expression of Lewisy/b antigens is associated with decreased survival in lymph node negative breast carcinomas [J].
Madjd, Z ;
Parsons, T ;
Watson, NFS ;
Spendlove, I ;
Ellis, I ;
Durrant, LG .
BREAST CANCER RESEARCH, 2005, 7 (05) :R780-R787
[39]   Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma [J].
Posey, Avery D., Jr. ;
Schwab, Robert D. ;
Boesteanu, Alina C. ;
Steentoft, Catharina ;
Mandel, Ulla ;
Engels, Boris ;
Stone, Jennifer D. ;
Madsen, Thomas D. ;
Schreiber, Karin ;
Haines, Kathleen M. ;
Cogdill, Alexandria P. ;
Chen, Taylor J. ;
Song, Decheng ;
Scholler, John ;
Kranz, David M. ;
Feldman, Michael D. ;
Young, Regina ;
Keith, Brian ;
Schreiber, Hans ;
Clausen, Henrik ;
Johnson, Laura A. ;
June, Carl H. .
IMMUNITY, 2016, 44 (06) :1444-1454
[40]   Cytokines as potential combination agents with PD-1/PD-L1 blockade for cancer treatment [J].
Rahimi Kalateh Shah Mohammad, Ghasem ;
Ghahremanloo, Atefeh ;
Soltani, Arash ;
Fathi, Esmat ;
Hashemy, Seyed Isaac .
JOURNAL OF CELLULAR PHYSIOLOGY, 2020, 235 (7-8) :5449-5460