Drug Targeting Organ-Specific Strategies Edited by Grietje Molema ...

9.3 Tumour Vasculature Targeting and Pre-clinical Experience 247
the conjugated doxorubicin caused vascular damage in the tumours and a strong anti-tumour
effect at a 10–40 x lower concentration than that of free doxorubicin, while liver and heart
toxicity was reduced compared to that observed with free doxorubicin [90]. Whether this effect
was caused by the selective delivery of the chemotherapeutic drug to the tumour endothelial
cells and/or tumour cells, direct caspase-3 activation [91], or a combination, has not
as yet been established.Their results illustrate the potential of targeting therapeutic agents to
integrins expressed on the vasculature of tumours as an effective means of cancer treatment.
9.3.4 Tumour Vasculature-specific Blood Coagulation Induction
Toxins as effector molecules have been widely studied in vitro and applied in vivo in pre-clinical
and clinical studies. A frequent observation with immunotoxins in the clinic is the occurrence
of vascular leak syndrome. This toxicity is associated with the toxin moiety of the immunotoxin
and sometimes demands cessation of therapy or administration of sub-optimal
dosages [92]. Another approach with high potential is to selectively inhibit tumour blood
flow by selectively targeting the blood coagulation-inducing activity of the tumour endothelium.
In one study on coagulation-inducing capacity, a mouse model for tumour vasculature was
exploited in which the expression of MHC Class II was artificially induced on tumour endothelial
cells [93]. Bispecific antibodies (BsAb) against MHC Class II and a truncated form
of the activator of the extrinsic coagulation pathway, truncated Tissue Factor (tTF), were
chemically prepared. Intravenous administration of a mixture consisting of BsAb and tTF
(BsAb * tTF), the so-called ‘coaguligand’ formulation, to mice with clinically relevant tumour
burden, resulted in dramatic tumour reduction without concurrent toxicity in other organs
(Figure 9.3). Site-specific blood coagulation in the tumour blood vessels caused an almost
instantaneous and persisting blockade of tumour blood flow.Treatment of mice bearing
Figure 9.3. Photograph of a mouse 7 days after i.v. injection of a coaguligand formulation consisting of
truncated Tissue Factor mixed with a bispecific antibody directed at the MHC Class II molecules on the
tumour vasculature and at truncated Tissue Factor. The mouse carried a C1300 muγ tumour measuring
approximately 10 x 10 mm in diameter at the time of treatment. Within hours after treatment the tumour
blood flow was blocked by generalized blood coagulation in the tumour vasculature (not shown). Seven
days after treatment, the necrotic tissue was almost completely removed by the host immune cells.