Antibody Molecules, Genetic Engineering of
345
Fig. 8
Schematic representation of
antibody fusion proteins. (a) to (c)
represent different antibody fusion
proteins in which the nonantibody
partner was fused at the
carboxy-terminus after the C
H
3doma
in
(a), immediately after the hinge (b), or
after the C
H
1 domain (c). (d) to (f)
represent antibody fusion proteins in
which the nonantibody partner has been
joined to the amino-terminus of the
full-length heavy chain (d) or the
truncated heavy chain (e and f). (g) and
(h) represent two fusion proteins with
the nonantibody partner fused to the
amino-terminus of the C
H
1doma
in(g)
or immediately before the hinge (h).
NH
2
COOH
NH
2
COOH
(a)
(b)
(c)
(d)
(e)
(g)
(h)
(f)
NH
2
COOH
An alternative approach is to construct
antibody fusion proteins with the ligand
fused to the amino-terminus of the heavy
chain (Fig. 8 d–f). This may be neces-
sary for proteins that require N-terminal
processing or folding for activity such as
nerve growth factor (NGF), the costimu-
latory molecule B7.1, and interleukin-12
(IL-12). In fact, antibody-NGF, antibody-
(B7.1), and antibody-(IL-12) fusion pro-
teins containing the ligand fused to the
amino-terminus of the antibody retain
both the ability to bind antigen and the
activity of the nonantibody partner.
Nonantibody sequences can also be used
to replace the V
H
domain or the V
H
–C
H
1
domains (Fig. 8 g and h). These molecules,
which lack the ability to bind antigen, have
been called
immunoadhesins
because they
c
on
t
a
inanadh
e
s
i
v
em
o
l
e
cu
l
el
in
k
edt
o
the immunoglobulin Fc effector domains.
In these proteins, the fused moiety ac-
quires antibody-associated properties such
as effector functions or improved phar-
macokinetics. An example is the tumor
necrosis factor (TNF) receptor IgG fusion
protein, which binds to TNF (a mediator of
inflammation) and neutralizes its activity.
In fact, this molecule has been demon-
strated to be ef±cacious for the treatment
of rheumatoid arthritis.
Although Fig. 8 shows the nonantibody
partner fused to the heavy chain, it should
be appreciated that the nonantibody part-
ner can also be fused to the light chain. It
is also possible to construct antibody fu-
sion proteins that combine more than one
kind of nonantibody partner at the amino-
or carboxy-termini of the heavy and/or
light chains. In addition, a nonantibody
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