Biomedical Engineering Reference
In-Depth Information
TABLE 6.2
Therapeutic Antibodies Approved by the FDA for Targeted Cancer Therapy
Trade
Name
Molecular
Target
Year of FDA
Approval
Generic Name
Type
Indication
Monoclonal antibodies
Rituximab
Rituxan
Chimeric
CD20
Low-grade B-cell
non-Hodgkin's lymphoma
1997
Trastuzumab
Herceptin
Humanized
HER2
Metastatic breast cancer
1998
Alemtuzumab
Campath
Humanized
CD52
Chronic lymphocytic
leukemia
2001
Bevacizumab
Avastin
Humanized
VEGF
Metastatic colorectal
cancer
2004
Cetuximab
Erbitux
Chimeric
EGF
receptor
Metastatic colorectal
cancer
2004
Immunoconjugates
Gemtuzumab
ozogamicin
Mylotarg
Humanized
CD33
Acute myeloid leukemia
2000
Ibritumomab
tiuxetan
Zevalin
Murine
CD20
Relapsed or refractory
non-Hodgkin's lymphoma
2002
Tositumomab and
131
I tositumomab
Bexxar
Murine
CD20
Non-Hodgkin's lymphoma
refractory to Rituximab
and relapsed following
chemotherapy
2003
Source
: Brannon-Peppas, L. and Blanchette, J.O.,
Adv
.
Drug Del
.
Rev
., 56, 1649-1659, 2004; Schrama, D., Reisfeld,
R.A., and Becker, J.C.
Nat
.
Rev
.
Drug Discovery
, 5, 147-159, 2006. Bicknell, R.,
Br
.
J
.
Cancer
, 92, S2-S5,
2005.
delivery potentials in biomedical processes. The Tfs are typically monomeric glycoproteins with a
single polypeptide chain of 670-700 amino acids and a molecular weight of ca. 80 kDa [87].
The transferrin receptor (TfR) assists iron uptake into vertebrate cells through a cycle of
endo and exocytosis of Tf. It appears to be expressed in all nucleated cells and has been found
in red blood cells, thyroid cells, hepatocytes, intestinal cells, monocytes, brain, the blood-brain
barrier, and also in some insects and certain bacteria. Elevated levels of TfR expression in malig-
nant cells is attributed to the requirement of a high iron level for their growth [87,88]. A sche-
matic representation of the endocytosis and recycling cycle for the Tf/TfR complex is given in
Figure 6.4. First, Tf binds two Fe
3
+
atoms per molecule. TfR subsequently binds the iron-loaded
Tf, and the Tf/TfR complex is internalized through clathrin-coated pits. Tf releases iron in the
acidic endosomal environment, and the Tf/TfR is recycled back to the plasma membrane. Then,
the iron-free Tf is released from TfR to complete the cycle [88]. Many anticancer agents have
been considered for conjugation to Tf by varying methods, including direct chemical linkage,
liposomal packaging of toxin, conjugation of DNA-polylysine complexes, and conjugation of
liposome-DNA complexes. For example, methotrexate that has been formulated in a liposome
complex and conjugated to Tf demonstrated a higher effi ciency of cellular uptake and cytotoxicity
compared to the control free methotrexate and methotrexate-liposome [46]. Huwyler et al.
demonstrated that daunomycin-containing liposomes conjugated to OX26 rat TfR antibody
exhibit an increased delivery and uptake in the central nervous system relative to the non-OX26
containing liposomes [47,88].
