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Title: Intestinal stability and permeability of anti-TNF α monoclonal antibodies
Author: Yadav, Vipul
ISNI:       0000 0004 6423 7525
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Monoclonal antibodies (mAbs) are one of the fastest growing classes of biotherapeutic agents, which are used in the treatment and diagnosis of a wide range of diseases, including cancer diagnosis, inflammatory and autoimmune diseases. One of the drawbacks with this class of therapeutics; however, is the need for parenteral administration due to their perceived instability in the gastrointestinal (GI) tract. The aim of this thesis was to explore the potential for local delivery of the anti-TNF α IgG1 mAbs infliximab and adalimumab in the colon, with potential applications in the oral treatment of inflammatory bowel disease (IBD). The work involved a thorough investigation of the human GI luminal stability of the mAbs; the molecules showed high stability in colonic fluid as compared to the rapid degradation observed in human gastric and small intestinal fluids. The mAbs and their respective Fab fragments were then tested for their ability to penetrate the colon tissue using a rodent model. Deep penetration of infliximab, adalimumab and their respective Fab fragments into the colonic tissue was observed with drug signal detected in both the mucosal and submucosal regions. Mechanistic investigations revealed the role of colonic FcRn receptors in the cellular transcytosis of the mAbs. The ability of antibody to penetrate the colon tissue was also shown in a DSS colitis mouse model of IBD. Overall the results are promising and indicate that IgG1 mAbs not only survive the hostile luminal environment of the large intestine, but also penetrate the colon tissue barrier to allow maximal local exposure of the therapeutic antibody to bind the overexpressed proinflammatory target TNF-α in IBD.
Supervisor: Basit, A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available