Hydrolytically Stable Site-Specific Conjugation at the N-Terminus of an Engineered Antibody

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• 作者：Pamela Thompson ; Binyam Bezabeh ; Ryan Fleming ; Monica Pruitt ; Shenlan Mao ; Patrick Strout ; Cui Chen ; Song Cho ; Haihong Zhong ; Herren Wu ; Changshou Gao ; Nazzareno Dimasi
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：October 21, 2015
• 年：2015
• 卷：26
• 期：10
• 页码：2085-2096
• 全文大小：668K
• ISSN：1520-4812

文摘

Antibody鈥揹rug conjugates (ADCs) have emerged as an important class of therapeutics for cancer treatment that combine the target specificity of antibodies with the killing activity of anticancer chemotherapeutics. Early conjugation technologies relied upon random conjugation to either lysine or cysteine residues, resulting in heterogeneous ADCs. Recent technology advancements have resulted in the preparation of homogeneous ADCs through the site-specific conjugation at engineered cysteines, glycosylated amino acids, and bioorthogonal unnatural amino acids. Here we describe for the first time the conjugation of an anti-mitotic drug to an antibody following the mild and selective oxidation of a serine residue engineered at the N-terminus of the light chain. Using an alkoxyamine-derivatized monomethyl auristatine E payload, we have prepared a hydrolytically stable ADC that retains binding to its antigen and displays potent in vitro cytotoxicity and in vivo tumor growth inhibition.