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Title: Study into the role of lactadherin as a tumour associated antigen and angiogenesis factor : investigating HuMc3 (Angiolix®) as a therapeutic antibody for cancer
Author: Bonney, Laura Catherine
ISNI:       0000 0004 2700 129X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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Lactadherin is a glycoprotein thought to have roles in cancer progression, through ligation of integrins αvβ3 and/or αvβ5 on the surface of tumour cells and their vasculature. It is thought to promote tumour growth through activation of integrin signalling pathways in both tumour and vascular endothelial cells, leading to direct tumour expansion and indirect tumour growth through stimulation of angiogenesis. HuMc3 (Angiolix®) an antibody with affinity to the integrin binding EGF-like domain of lactadherin, has been shown to inhibit lactadherin association with αv integrin expressing cell lines. This work aimed to uncover whether through its disruption of lactadherin αvβ3 and/or αvβ5 integrin ligation, HuMc3 could prevent/slow the growth of lactadherin-overexpressing tumours. This work confirmed the ability of HuMc3 to inhibit lactadherin binding to both tumour cell and vascular endothelial cell αvβ3/αvβ5 integrins. It demonstrated a concentration-dependent growth inhibition of tumour xenografts in vivo alone and a greater effect for combination with a conventional chemotherapy drug than either therapy alone. In one tumour model HuMc3 showed a similar therapeutic effect when applied alone to an approved anti-vasculature anti-cancer therapeutic bevacizumab, though a lower effect was observed when both were applied with chemotherapy. HuMc3 showed no apparent therapeutic toxicity and in biodistribution studies, no specific uptake by any normal murine tissue. In addition, the in vivo data for HuMc3 compared fairly well with that published for other anti-cancer and anti-vasculature therapeutics approved/in clinical development. HuMc3 was therefore indicated to have the potential as a successful anti-cancer therapeutic for treatment of lactadherin over-expressing cancers. Further work may determine the optimal monotherapy concentration and may uncover better combinations with other targeted agents and conventional chemotherapy/radiotherapy. A major drawback of this work was however the lack of success of the in vitro assays, so the mode of action of HuMc3 could not be confirmed. Further work may involve repeating these assays under conditions shown successful in published work with other αvβ3/αvβ5 integrin ligand-mAb combinations, as well as repeating the in vivo work with inclusion of an isotypematched control antibody, tissue analysis to examine any changes to vascular density and with examination of the importance of antibody effector functions in the in vivo effect of HuMc3
Supervisor: Deonarain, Mahendra Sponsor: Access Pharmaceuticals/Somanta ; Biotechnology and Biological Sciences Research Council, (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral