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Antibody conjugates : integrated approach towards selective, stable and controllable bioconjugation

Abstract : Within the last decade, antibodies conjugated to cytotoxic drugs or oligonucleotides have gained a great attention in scientific community owing to the unique properties of the antibodies, such as their long circulation time in serum and high selectivity against their target. For instance, antibody conjugates (ACs) are increasingly applied for targeted cancer therapy or bioimaging. Consequently, the development of reliable methodologies for ACs preparation is currently of high demand. However, the controllable conjugation and preparation of ACs with defined structure are still challenging due to high excess and variety of reactive groups in antibody structure, which are accessible for conjugation. Moreover, current linker technologies are based on the maleimide-thiol reaction, yielding adducts, which are unstable during circulation in blood.This work is focused on chemical approaches for the reliable antibody functionalisation, which enable the preparation of stable ACs with well-defined payload to antibody ratios. The first part is devoted to design and development of maleimide-dioxane reagents as self-hydrolysable and serum-stable alternative to classical maleimide chemistry. The second part is dedicated to a screening approach for evaluation of residue-selective functionalities in reactions with an antibody using high resolution native mass spectrometry. Finally, in the third part the reader is introduced with a novel technology, which enables efficient preparation of stable ACs with a defined degree of conjugation and particularly mono-functionalisation of antibodies.
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Submitted on : Thursday, June 18, 2020 - 3:08:16 AM
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  • HAL Id : tel-02872896, version 1



Igor Dovgan. Antibody conjugates : integrated approach towards selective, stable and controllable bioconjugation. Organic chemistry. Université de Strasbourg, 2017. English. ⟨NNT : 2017STRAF036⟩. ⟨tel-02872896⟩



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