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

Bioconjugate Chemistry
Pamela ThompsonNazzareno Dimasi

Abstract

Antibody-drug 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.

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Citations

Jan 27, 2016·Journal of Bioscience and Bioengineering·Jinhua DongHiroshi Ueda
Jul 7, 2016·Organic & Biomolecular Chemistry·Richard J Spears, Martin A Fascione
Jan 18, 2019·Angewandte Chemie·Sebastian PomplunFrank Bergmann
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Dec 9, 2020·Chemical Society Reviews·Stephen J WalshDavid R Spring
Mar 2, 2021·Antibody Therapeutics·Amissi SadikiZhaohui Sunny Zhou
Nov 25, 2016·ACS Medicinal Chemistry Letters·Pamela ThompsonNazzareno Dimasi
May 16, 2019·Bioconjugate Chemistry·Dana N ThornlowChristopher A Alabi
Sep 15, 2021·Chembiochem : a European Journal of Chemical Biology·Karl D BruneKaspars Tārs

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