Organic and Biomolecular Chemistry p. 7261 - 7269 (2014)
Update date:2022-08-02
Topics:
Schumacher, Felix F.
Nunes, Joao P. M.
Maruani, Antoine
Chudasama, Vijay
Smith, Mark E. B.
Chester, Kerry A.
Baker, James R.
Caddick, Stephen
The advent of Adcetris and Kadcyla, two recently FDA-approved antibody-drug conjugates (ADCs), in the clinic has had a major impact on the treatment of lymphoma and breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages of development, often due to shortcomings in the methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds and allow the efficient conjugation of small molecules to antibodies, without the need for engineering of the target antibody. The method is site-specific and generates near homogeneous products in good yields. Moreover, adjustment of the reaction conditions allows control of the conjugation in terms of stoichiometry (drug-loading) and site selectivity. Using this method we prepared a series of ADCs from trastuzumab and doxorubicin (DOX) with a controlled drug-to-antibody ratio (DAR) of 1, 2, 3 and 4. All of these constructs were fully active by ELISA and had more than 90% of re-bridged disulfide bonds by CE-SDS when compared to clinical grade antibody. Furthermore, digest experiments of the DAR 2 material revealed that almost all of the drug had been targeted to the Fab arms of the antibody. Thus, NGMs offer a flexible and simple platform for the controlled assembly of ADCs from an antibody. This journal is the Partner Organisations 2014.
View MoreShanghai Pinewood Fine Chemical Co., Ltd.
website:http://www.pinewoodchem.com
Contact:0086-21-62417129,62414096
Address:Suite B, 27F, No.2, Lane 600, Tianshan Road, Shanghai
Rugao Jinling Chemical Co., Ltd.(expird)
Contact:0086-513-68005586
Address:Lianluo new village huangshi town Rugao city Jiangsu Province.
Tangshan Wisdom Trading Co.,Ltd
Contact:86 315 2222979
Address:No.41 BeiXinXi Road, Yangguang building 1-1102 , Tangshan, Hebei, China
Hangzhou Ocean Chemical Co., Ltd.
website:http://www.hzoceanchem.com
Contact:+86-571-88025872, 28272092, 28272096
Address:Room 623 ,Building No 1 , COFCO Radius Commercial Center Xiwen Road, Xiacheng District, Hangzhou, Zhejiang Province, China
website:http://www.josunpharma.com
Contact:+86-311-80715268 80766839
Address:No.39, Zhaiying Street, Shijaizhuang,Hebei,China
Doi:10.1002/chem.201302437
(2013)Doi:10.1021/ml3003633
(2013)Doi:10.1246/cl.2012.1675
(2012)Doi:10.1021/ja311783k
(2013)Doi:10.1039/c5gc01931a
(2016)Doi:10.1007/s10593-013-1175-7
()