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

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• King, Thomas

Advisor dc:contributor.advisor

• Spring, David

• ADC
• Antibody
• Bioconjugation
• Chemistry
• Linker
• TetraDVP

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c569c3ce-5f13-4d25-958f-a615be76d19b/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0001-6992-8016

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/355950