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Title: Using structural fragments to design antibody binding sites
Author: Regep, Cristian
ISNI:       0000 0004 7430 5907
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Antibodies are an essential part of the immune system. They are able to attain high specificity and affinity to almost any antigen, and through their modularity make a robust framework for protein engineering. As a result, development of therapeutic antibodies has grown rapidly and they now account for the majority of revenue in the sales of new bio-therapeutics. The established design methods are heavily based on experimental simulation of the antibody maturation process outside of the human organism, and make little use of rational computational design methods. In this thesis we analysed the applicability and issues surrounding an existing modelling paradigm and developed a novel approach towards de novo antibody design. The majority of the affinity and specificity of antibodies is modulated by a set of six binding loops called the Complementarity Determining Region (CDR). We analysed the proportion of antibody CDRs that can be modelled in a set of 15 million antibody sequences. Out of all the CDRs H3 is the only one where we observed a large number of sequences that can not be modelled accurately. We then further explored why CDR H3 is so hard to model and found that the reason is not method dependent, but is a result of a lack of suitable structures. The H3 CDR shows unique structural characteristics at full loop, four residue and single residue levels of granularity. On the topic of de-novo antibody design we developed SAbDesigner, an automated computational pipeline for designing antibodies by mimicking the binding interface of a receptor of the target protein on the CDR. SAbDesigner automatically identifies important loops for binding on the receptor and then identifies an antibody framework that is able to accommodate it through loop grafting. The designs are then computationally validated, further refined using both point mutations, and optimisations of other CDRs. Through this pipeline we proposed a set of 15 novel antibodies that target Interleukin-5, an important therapeutic target, and also performed an applicability study across other major important therapeutic targets.
Supervisor: Deane, Charlotte Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available