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Exploration of novel linker scaffolds enabling the simultaneous rebridging of disulfide bonds for the synthesis of antibody-drug conjugates


Type

Thesis

Change log

Authors

Abstract

Antibody-drug conjugates (ADCs) are a class of targeted therapeutic, typically used for the treatment of cancers. By attaching drugs site-selectively to antibodies, off-target toxicity of the drug can be reduced, leading to significant benefits for the patient. In order to improve the homogeneity of ADCs, in particular their drug-to-antibody ratio (DAR) and the mixture of protein species present, a linker reagent known as TetraDVP, which simultaneously rebridges all interchain disulfide bonds in an IgG1 antibody, has been developed and was recently reported by the Spring Group.

The work reported in this thesis explores the translation of this ‘all-in-one’ rebridging linker technique to the generation of azide-containing antibody-linker conjugates (ALCs). Synthesis of alternative linker scaffolds is reported, along with the corresponding assessment of their capabilities to rebridge the IgG1 antibody trastuzumab after interchain disulfide reduction. Application of post-conjugation click chemistry enables the synthesis of ADCs more efficiently than has been previously observed using TetraDVP linkers.

Description

Date

2023-02-22

Advisors

Spring, David

Keywords

ADC, Antibody, Bioconjugation, Chemistry, Linker, TetraDVP

Qualification

Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge
Sponsorship
BBSRC (2126305)