Drug Targeting Organ-Specific Strategies

cells, the presence of co-stimulatory molecules such as CD28 and cytokines is a prerequisite
to achieve this, whereas granulocytes and macrophages can be activated with granulocyte
macrophage colony stimulating factor (GM-CSF).
Heteroconjugates made by cross-linking two different IgGs are twice as large as MAbs
and thus are limited in their ability to penetrate tumours, although this problem can be
solved by combining two different scFvs resulting in BsMAb formats with minimal molecular
mass.As is the case for all mouse Mab-based therapies, HAMA is generated, but with the
help of humanizing and chimerizing technologies this should become less of a problem in the
future.
8.5.3 Pro-drug Strategy
8.5.3.1 Antibody-directed Enzyme Pro-drug Therapy (ADEPT)
Pro-drugs in combination with enzyme–MAb conjugates can also be used to target tumour
cells [81,82]. The so-called antibody-directed enzyme pro-drug therapy (ADEPT) approach
involves the use of antibody–enzyme conjugates directed against tumour-associated antigens
that achieve in situ activation of subsequently administered pro-drugs. Pro-drugs are inactive
drug precursors that are not readily taken up by cells and hence are less toxic to healthy cells.
The pro-drug can be converted locally in the tumour into the active drug by a specific enzyme
which is covalently linked to tumour-specific antigen-targeted MAbs. When the active form
of the drug is released, it will then distribute to the nearby tumour cells, resulting in cell
death. A number of such pro-drug/MAb–enzyme conjugates have been developed and tested
in vitro and in vivo [83,84]. One of the significant advantages of this approach is that the
targeted enzyme can be effective without being endocytosed. Another beneficial aspect is
that a large amount of the drug can be enzymatically generated at the tumour site. Table 8.4
shows some ADEPT strategies developed in recent years. Limitations of ADEPT include
suboptimal tumour uptake due to heterogeneity in antigen expression, development of immune
responses against the enzyme component, the risk of diffusion of the active drug away
from the tumour site and the complexity of dosing schedules.
8.5.3.2 Pro-drug Monotherapy
8.5 Strategies to Deliver Drugs to Targets within the Tumour (Cells) 217
Another pro-drug strategy under development is the concept of ‘monotherapy’. An attractive
feature of pro-drug monotherapy, unlike ADEPT, is that antibody–enzyme conjugates
are not required. In the case of pro-drug monotherapy, local production of elevated levels
of enzymes by the tumour is exploited to release the active drug. Pro-drug monotherapy
works well with anthracycline pro-drugs that are activated by β-glucuronidase [85,86] which
can be found in elevated concentrations in necrotic areas of tumour tissue [87]. De Groot
et al. [88] also developed anthracycline pro-drugs that can be activated by the tumour-associated
protease plasmin. The plasmin system plays a key role in tumour invasion and metastasis
by its matrix degrading activity and its involvement in tumour growth, most likely by its
participation in growth factor activation and angiogenesis.