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