Biomedical Engineering Reference
In-Depth Information
19
TARGETED AND UNTARGETED FUSION PROTEINS:
CURRENT APPROACHES TO CANCER IMMUNOTHERAPY
L
ESLIE
A. K
HAWLI
,
1
P
EISHENG
H
U
,
2
AND
A
LAN
L. E
PSTEIN
2
1
Department of Pharmacokinetic and Pharmacodynamic Sciences, Genentech Research and Early Development,
Genentech, Inc, San Francisco, CA, USA
2
Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
19.1 Introduction
19.2 Immunotherapeutic strategy for cancer: fusion proteins
19.3 Immunotherapeutic applications of antibody-targeted and
untargeted Fc fusion proteins
19.4 Combination fusion proteins therapy
19.5 Mechanism of action: immunoregulatory T-cell (T
reg
)
depletion and fusion protein combination therapy
19.6 Future directions
19.7 Conclusion
Acknowledgments
References
valency, amino acid composition, and carbohydrate content)
has been considerably extended and therefore helped the
intelligent design to improve their pharmacological propert-
ies [1]. The full IgG molecule is a tetramer composed of two
light chains (LCs) and two heavy chains (HCs) assembled in
the “Y” shape motif. The LCs contain an N-terminal varia-
ble domain and a C-terminal constant domain, while the
HCs consist of a variable N-terminal domain and three to
four C-terminal constant domains. The Fab domain (antigen
binding fragment) is composed of the LC and the first two
N-terminal domains of the HC. The Fc region (crystallizing
fragment) is a dimer of the two or more C-terminal domains
of the HC that are not part of the Fab. The Fc regulates the
biological functions of the antibody by binding to Fc
receptors and eliciting immune effector functions. Of par-
ticular importance for therapeutic mAbs, the Fc portion of
IgG binds pH-dependently to the neonatal Fc receptor
(FcRn), which protects mAb from degradation and partially
accounts for their long serum half-lives [2]. The unique
complementarity-determining regions (CDRs) usually
define the antigen specificity and reside in the variable
fragment (Fv) portion of the Fab. There are four human
IgG subclasses (IgG1, IgG2, IgG3, and IgG4), which are
distinguished from one another by differences in the con-
stant region of the HC sequence. Different IgG subclasses
bind to different Fc receptors with varying affinities. Thus,
IgGs of one subclass may be more or less efficient at
eliciting certain effector functions than IgGs of another
subclass.
As advances in antibody engineering, including hybri-
doma and phage-display technologies, have enabled the
19.1
INTRODUCTION
The generation of monoclonal antibodies (mAbs) has
resulted in major therapeutic advances across a spectrum
of diseases, including cancer, inflammatory, and auto-
immune diseases. Antibodies or immunoglobulins (Ig) are
generally multifunctional glycoproteins that are produced
and secreted by plasma cells and are capable of binding with
high affinity and specificity to foreign substances known as
antigens. In humans, there are five major classes of anti-
bodies: IgG, IgA, IgD, IgE, and IgM that differ from each
other based on their structure and immune function. The IgG
class, whose molecular weight is
150 kDa, is the principle
Ig that participates in the adaptive immune response and
comprises
85% of the Ig in normal human serum. The
detailed knowledge of antibody structure (e.g., size, charge,
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