Biomedical Engineering Reference
In-Depth Information
tumor cells not expressing the targeted antigen, as long as
the cells are in proximity to the released activated drug [62].
In some cases, even catalytic antibodies have been used for
prodrug therapies. Taking into account this recent progress,
bispecific antibodies combining targeting with enzymatic
activity could become feasible [63]. A more detailed over-
view of ADEPT is given in Chapter 23.
and autocatalytically activating caspase 8 and 10 that in
turn activate a series of other caspases that ultimately
perform cell killing. Owing to the involvement of extrac-
ellular ligands, this pathway is called extrinsic pathway.
Addressing this pathway through death receptor ligands is an
attractive therapeutic approach since here apoptosis is
induced independently of the tumor suppressor p53, which
is frequently nonfunctional in human cancer cells [64].
Obstacles that might prevent the utilization of the soluble
TNF such as ligands are their relative short half-life, their
tendency to form high molecular aggregates, and their
systemic toxicity. However, most of the problems can be
addressed by an intelligent design of fusion proteins. A
schematic overview on apoptosis pathways is presented in
Figure 17.3.
17.5 APOPTOSIS INDUCTION
Another possibility to destroy malignant cells is to trigger
apoptosis through death receptors (DR) that belong to the
TNF receptor superfamily. The receptors contain a cyto-
plasmic death domain (DD) and can transduce an extrac-
ellular signal that results from binding of a suitable ligand
into intracellular protease-mediated cell death. Homotri-
meric ligands such as the tumor-necrosis factor-related
apoptosis-inducing ligand (TRAIL) induce receptor oligo-
merization and the activation of a proteolytic cascade, which
involves maturation of caspases. The adapter protein FADD
(Fas-associated protein with death domain) generates a
death-inducing signaling complex (DISC) by recruiting
17.5.1 TNF Fusion Proteins
Directly targeting death receptors with their respective
ligands seems to be a promising solution for targeted
therapy. As a first candidate, TNF itself was selected.
The primary function of TNF is not necessarily direct killing
of cancer cells but rather the destruction of vasculature.
FIGURE 17.3 Apoptosis induction. Binding of death receptor (DR) ligands such as tumor necrosis
factor (TNF), TRAIL, or FasL, triggers the formation of a death-inducing signaling complex (DISC)
at their death domains (DD) that interact with Fas-associated death-domain (FADD) and activates
caspase-8. This protease truncates BID to form tBID, which connects the extrinsic with the intrinsic
pathway. tBID or the p53-induced oligomerization of Bax and Bak cause cytochrome C (CytC)
release which triggers ultimately the activation of caspase-9. This protease links the intrinsic with the
extrinsic pathway by activating caspase-3 that degrades ICAD to release CAD which in turn causes
cell death by DNA fragmentation. Several important molecules such as BID, caspase-3, and ICAD
can also be activated by granzyme B (GrB), which can enter the cell during inflammation through
perforin pores.
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