Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.756000
Title: Pyridazinediones : a novel class of tuneable reagents for the selective dual modification of proteins
Author: Maruani, A. G. F.
ISNI:       0000 0004 7428 9572
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Abstract:
Antibody–drug conjugates (ADCs) are a particularly promising class of antibody-based therapeutics. They are commonly referred to as “magic-bullet” therapy due to the ability to seek and destroy primarily diseased cells within the body (e.g. cancer cells). Critical to this strategy is the availability of effective methodologies to link an antibody to other molecules (e.g. cytotoxic drugs, prodrugs). Although current approaches offer great promise for the development of ADC constructs, they often are not selective and yield heterogeneous product mixtures. Other strategies require mutations with natural or unnatural amino acids, which are generally associated with low expression yields and post-translational issues, whilst some result in the loss of vital disulfide bonds. Furthermore, most of the current peptide/payload linker technologies have the potential to attach only one moiety, greatly limiting their scope and flexibility. To tackle these issues, a novel class of tuneable reagents based on pyridazinedione (PD) moieties was developed. These reagents are readily accessible from inexpensive starting materials in 3 – 4 scalable steps and overcome the problems stated above. Indeed, the PD-based reagents have exquisite selectivity towards cysteines over lysines, even at high temperature and/or with an excess of reagent. When reacted with reduced native disulfide bonds of antibodies or antibody fragments, PDs rapidly and quantitatively form a stable and rigid 2-carbon bridge between the two cysteines side-chains without affecting the structure and biological activity of antibodies. The resulting conjugates have also been demonstrated to have exceptional resistance to hydrolysis at various extreme pHs and temperatures over an extended period of time. Finally, the PD-conjugates possess two orthogonal handles that were readily modified with two different moieties to generate highly functionalised homogeneous constructs with application not only in antibody therapeutics but also in imaging and diagnostics.
Supervisor: Caddick, S. C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.756000  DOI: Not available
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