Biomedical Engineering Reference
In-Depth Information
Several approaches have been reported exploiting the overexpression of antigens
and or receptors in specific cancers, these include targeting the epidermal growth
factor receptor (EGFR) [
39
,
40
], the human epidermal growth factor receptor
(HER2) [
41
-
43
] or the glucagon-like receptor (GLP-1R) [
44
] as well as numerous
cell surface epitopes [
45
,
46
] to name but a few. Furthermore, Auger emitter labeled
mAbs may be better suited to treat hematological malignancies compared to solid
tumors due to their limited range, preliminary studies have shown promising results
[
47
,
48
]. A major disadvantage of radioimmunotherapy (RIT) is that the antigen
being targeted is not always expressed homogeneously in the cancer cell resulting
in heterogeneous dose distribution in the target tissue [
49
]. Another limitation,
highlighted by the results of clinical studies using murine mAbs, was the pro-
duction of human anti-murine immunoglobulin antibodies (HAMA), after repeated
administration [
37
]. This limitation can be addressed by chemical modification of
the mAbs, through production of chimeric mAbs, or complete humanization of the
protein [
50
]. Another consideration, in the case of
125
I, it is not possible to deliver
the nuclide to the nucleus using directly radiolabelled antibodies which bind to cell
surface antigens as
125
I-labeled monoclonal antibodies are catabolized in lysosomes
ultimately yielding free
125
I-iodide which is rapidly excreted from the cells [
49
].
Therefore a molecular target that not only internalizes but is targeted to the nucleus,
or more specifically to the DNA is a requirement for inducing lethal lesions.
28.3.1.1
Epidermal growth factor receptor targeting
The EGFR is a cell surface signaling glycoprotein and the first member of the
Type 1 family of transmembrane peptide growth factor receptors which also
includes the HER2, HER3, and HER4 receptors [
51
,
52
]. Overexpression of EGFR
is common in many malignancies including cancers of the breast, ovary, head
and neck, lung, bladder, and colon as well as in glioblastomas [
53
]. Apart from
overexpression (up to 100 fold in some tumor cells compared to normal cells),
EGFR also plays a role in proliferation and is associated with poor prognosis,
which taken together makes EGFR an attractive therapeutic target [
54
]. Therapeutic
interventions exploiting the overexpression of EGFR include monoclonal antibodies
(mAbs) that block ligand binding and tyrosine kinase inhibitors that interfere with
receptor autophosphorylation and propagation of mitogenic signaling [
55
].
An extensively studied example of an Auger emitter using this targeting strategy
is that of
125
I-labelled mAb-425 [
56
-
60
]. The internalizing anti-EGFR antibody
mAb-425 was originally studied in the 90's as a new potential therapy for glioblas-
toma multiforme (GBM), an EGFR-positive aggressive brain tumor with limited
therapeutic options and high morbidity. mAb-425, proved successful in
in vitro
assays, as it reduced clonogenic survival of EGFR-overexpressing cells, in contrast
to cells with lower EGFR membrane expression [
61
].
125
I-mAb425 as well as
131
I-mAb-425 reduced tumor growth in mouse xenograft models. In a large phase
II clinical trial, a total of 192 patients with GBM were treated intravenously
with
125
I-mAb-425 following surgery and radiation therapy [
62
]. Treatment with
