Drug Targeting Organ-Specific Strategies

278 11 Development of Proteinaceous Drug Targeting Constructs
riers for renal drug delivery [12,13].A typical example of a protein that has been used for this
targeting purpose is lysozyme (LZM, 14 kDa) [14,15] (see Chapter 5 for a more detailed discussion
on the development of renal targeting preparations).
11.2.3 Monoclonal Antibodies
Monoclonal antibodies have been extensively reported on as carriers for targeted drug delivery.
Starting in the late 1970s, the production of monoclonal antibodies has now evolved
into a routine technique that has yielded many potential carrier molecules. Particularly in the
field of cancer therapy, monoclonal antibodies are being used for the delivery of diagnostic
and therapeutic agents [16] (see also Chapter 8). The original antibodies were of mouse origin,
evoking a human anti-mouse antibody (HAMA) immunological response when administered
in humans. The use of new recombinant techniques has enabled the preparation of
humanized antibodies, in which the mouse recognition domain has been grafted onto a human
antibody structure [17].
Whole IgG antibodies with a molecular weight of 150 kDa, are often unable to penetrate
tumour tissue as efficiently as smaller molecules [18]. Therefore, smaller antibody fragments
and genetically-engineered antibody derivatives have been investigated as drug carriers (see
Figure 11.5). These carrier molecules will be discussed in Section 11.8.1.
11.2.4 Transferrin
Some proteins are excellent carriers for drug targeting since they bind to more or less specific
receptors on the target cells. In addition to monoclonal antibodies, which in theory can
bind to any kind of receptor, several natural ligands for cell-surface receptors have been explored
as carrier proteins. This approach is exemplified by constructs that have been developed
for targeting via the transferrin receptor (TfR).The transferrin receptor is expressed on
most proliferating cells, as well as in a few non-proliferating tissues, among which is the endothelium
of brain capillaries. This distribution pattern has inspired the development of
transferrin-based constructs and anti-TfR antibodies as carriers for cancer therapy, as well as
for the delivery of compounds across the blood–brain barrier [19,20] (see also Chapter 2).
With respect to the latter, the ability of the TfR to undergo transcytosis results in the release
of the carrier complex in the brain, rather than in endocytosis by the endothelium of the
blood–brain barrier. Once inside the central nervous system, the drug delivery construct can
bind to TfR-positive cells, such as brain tumours, which can be regarded as a second step in
the delivery process.
As an alternative to targeting brain tumours which express the TfR, the transferrin approach
can be used for the delivery of fusion proteins which bind to pharmacological receptors
inside the central nervous system.An example of this is the construct consisting of nerve
growth factor (NGF) and transferrin described in Section 11.8.2.3. The transferrin moiety in
this type of construct will enable it to enter the brain, upon which the drug moiety will act by
binding to its receptor. This approach seems especially suitable for compounds that cannot
pass the blood–brain barrier, such as peptides and other hydrophilic substances.