Drug Targeting Organ-Specific Strategies

advances in this field are the development of antibodies against angiogenesis-associated factors
and receptors such as VEGF and integrin αvβ3 [56,57]. Furthermore, antibodies directed
against the CD3 molecule on T lymphocytes, a treatment developed for prevention of organ
rejection, are now under investigation for their immunomodulatory effects in cancer patients
[58].
Whereas initially the focus on antibody-based therapies was on cancer, anti-TNFα antibodies
in particular have recently proven powerful in the therapy of chronic inflammatory
diseases such as inflammatory bowel disease and rheumatoid arthritis [71]. These antibodies
complex serum TNFα, the clinical benefit to RA patients most likely being the reduction of
pro-inflammatory IL-6 and acute phase protein levels [9].Although they are directed against
soluble proteins and as such will not serve as a drug carrier, they do show that targeted, i.e.
selective, interference with a specific molecule or process can have a powerful effect without
significant concomitant toxicity.
Although in the early 1990s several antibodies were developed that inhibited leukocyte–endothelial
cell interaction to prevent e.g. allograft rejection or inflammatory processes
[72], more effort is nowadays put into the development of small molecule antagonists and antisense
oligonucleotides for this purpose [73,74]. A selection of more recently reported clinical
studies with antibodies is summarized in Table 1.2.
1.4.3 Monoclonal Antibody Based Targeting Strategies in the Clinic
Not only can antibodies by themselves function as targeted effector molecules, they can also
be used as carriers for the selective delivery of drugs, toxins, enzymes, radioisotopes, and adenoviral
vectors. Most of the strategies have been applied in humans [6,75–77]. Besides these
approaches, cellular cytotoxicity can be redirected towards the tumour cells using bispecific
antibodies that consist of a recognition site for specific cells of the immune system and tumour-associated
antigens [78,79]. This strategy circumvents the MHC restriction of antigen
recognition and cellular cytotoxicity. It may therefore be exploited for the therapy of tumours
which downregulate the expression of their MHC molecules and thereby avoid the
normal immune response.
In the development of these antibody-based targeting strategies, modifications that have
been applied to improve the efficacy of the therapy include the use of chimerized or humanized
antibodies, more potent drugs and better linkages between drugs and carrier molecules.
Furthermore, liposome encapsulation of drugs enabled a larger quantity of the drug to be delivered
per antibody molecule [75]. The development of transgenic mice capable of making
fully human antibodies now offers new opportunities for generating antibodies of therapeutic
quality, and as a result has led to the revival of interest in antibody-based therapies [80].
1.4.4 Other Drug Targeting Strategies in the Clinic
1.4 Drug Targeting Strategies in the Clinic 13
Of the non-antibody, non-liposome based drug targeting strategies, most of the (limited) clinical
experience has been obtained with polymer-based conjugates of anticancer drugs. The
most widely employed drugs for this application are cytotoxic agents such as doxorubicin and