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Title: Site-specific chemical modification of antibodies for the modulation of function
Author: Gunnoo, Smita B.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Chemical modification of antibodies is critical for many research areas including therapeutic and biotechnological applications. In particular, strategies for site-specific chemical modification via non-natural amino acids forming homogenous immunoconjugates are of interest. The use of fully functional single-domain antibodies derived from naturally occurring heavy chain antibodies in Camelidae species is attractive due to their enhanced properties, which are discussed in this piece of work. In terms of chemical antibody modification, much of the existing research is focused on modification away from binding regions, thus minimising disturbance to antibody function. In this thesis however, modifications within the binding region of the single-domain antibody cAb-Lys3 are described in a site-specific fashion with the aim of modulating binding affinities. An efficient and high yielding method for the expression and purification of cAh-Lys3 is described, followed by the site-specific installation of dehydroalanine, an electrophilic non-natural amino acid, able to react with nucleophiles that are inert to reaction with other proteinogenic amino acids. Then, the use of dehydroalanine as a unique reaction handle is explored. Firstly, the addition of short alkyl chains to dehydroalanine within the binding region of cAb-Lys3 is described with the aim of increasing hydrophobic interactions when binding to antigen.
Supervisor: Davis, Ben Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available