Drug Targeting Organ-Specific Strategies

248 9 Tumour Vasculature Targeting
carrier
molecule
fibrin
fibrinogen
tTF
tumor endothelium
specific target epitope
fVIIa
thrombin
prothrombin
tumor endothelial cell
Figure 9.4. Schematic representation of the mechanism of action of the coaguligand approach. Cross
linking of truncated Tissue Factor to tumour endothelial cells leads to local blood coagulation via the
tTF/fVIIa complex. tTF, truncated Tissue Factor; fVIIa, factor VIIa; fX (A), factor X (A).
subcutaneous tumours, twice with BsAb * tTF coaguligand led to 38% complete tumour regressions
and 24% partial responses [94]. The attractiveness of the coaguligand approach is
the use of a truncated form of TF which is devoid of coagulation-inducing activity as long as
it is prevented from complexing with the lipophilic factor X on cell membranes. Upon cross
linking of the hydrophilic tTF with the target cell membranes by the BsAb, tTF becomes
complexed with factor X. In the presence of factor VII/VIIa, this leads to the induction of
blood coagulation (Figure 9.4). It is thought that there is a threshold in the number of tTF
cross linked to cell membranes, above which the coagulation cascade is initiated. In theory,
this allows tumour endothelium-associated target epitopes to be utilized which are highly but
not exclusively, expressed on tumour endothelium. The level of expression on other vascular
beds is then too low to trigger coagulation after cross linking of the coaguligand.
Using a similar approach of tumour infarction, mouse solid Hodgkin’s tumours spontaneously
expressing endothelial VCAM-1 were significantly retarded in outgrowth [95]. The
anti-tumour effect was not as dramatic as seen in the MHC Class II model. Possibly, the number
of tTF molecules delivered at the site of the tumour endothelium was not sufficient to
create a rapid and more or less generalized pro-coagulant situation throughout the tumour
vasculature. Only if coagulation is induced in the majority of vessels, will the number of tumour
cells deprived of nutrients be sufficient enough to show strong anti-tumour effects. Furthermore,
anti-coagulation activities may be strong enough to counteract the coaguligand effects
when the kinetics of coagulation induction are insufficient to imbalance local pro- and
anti-coagulation activities.
The coagulation induction potency of coaguligand formulations are likely to be determined
by the following factors: (i) the number of target epitopes on the tumour endothelium
that allow BsAb-mediated interaction between tTF and factor X on the target cell membrane;
(ii) local anti-coagulation activity which may be regulated in a species-specific manner;
and (iii) the kinetics of cross linking of the BsAb and the target epitopes in relation to
the kinetics of coagulation induction capacity. The number of MHC Class II and VCAM-1
molecules expressed on the tumour vasculature of the animal models discussed, were high, as
were the affinities of the antibodies used. This enabled a significant number of tTF to be