Biomedical Engineering Reference
In-Depth Information
observed were proteinuria and fatigue. At all dose levels,
patients showed a dramatic increase in total serum Ang2
levels following administration of CVX-060, thus providing
a clinical proof of pharmacology and mechanism. Patients
were assessed radiographically for response per RECIST
criteria; of the 34 patients enrolled, 24 (71%) remained on
study
manufacturing issues but these scaffolds, with the exception
of DVD-Ig and the two in one antibody, suffer from poor
pharmacokinetics and therefore require frequent dosing or
conjugation to other scaffolds [28] to improve half-life.
Moreover, the complexity of generating new versions of these
scaffolds slows down the cycle time for their optimization and
lengthens the overall drug development time. CovX-Body
technology offers a chemical solution for the creation of bi-
specific antibodies referred to herein as bi-specific CovX-
Bodies [29]. Bispecific CovX-Bodies are created by using a
branched AZD linker that makes it possible to attach two
different pharmacophores on each Fab armas shown in Figure
38.8. This technology has been applied to the creation of
CVX-241 a bispecific CovX-Body that targets both Ang2 and
vascular endothelial growth factor (VEGF), two growth fac-
tors implicated in tumor angiogenesis.
VEGF plays a dominant role in tumor angiogenesis [30,31]
and its inhibition has been implemented clinically, mostly in
combination with chemotherapy, to treat cancers of the
intestine, liver, brain, colon, kidney, breast, and lung. How-
ever, in a majority of cases, the benefit to patients fromVEGF
inhibition is modest at best. Ang2, as discussed earlier, is
another major pro-angiogenic growth factor widely expressed
in renal, skin, colon, breast, and many other cancers. Ang2
plays a complementary role to VEGF in the tumor angiogen-
esis [32]. The increased expression of both VEGF and Ang2
has also been shown to correlate with poor survival [33]. In
human tumor, xenograft studies in mice, the physical combi-
nation of VEGF, and Ang2 antagonists showed enhanced
efficacy relative to the use of either single agent [18]. Thus,
simultaneous inhibition of both VEGF and Ang2may provide
better benefit to patients with cancers that express both VEGF
and Ang2 than inhibiting either VEGF or Ang2 alone. Physi-
cal combination of VEGF and Ang2 antagonists is, however,
greatly hindered by a number of factors including the high
8 weeks. In addition to the radiographic assessment,
DCE-MRIs were conducted in selected patients to assess the
effect of CVX-060 on tumour blood flow [20]. There were
significant mean decreases in K
trans
as measured by DCE-
MRI at Day 4 (p
0.0025) in 11
patients with data available at all 3 time points. A total of 10
out of 11 patients had decreases in K
trans
with mean decreases
of 12.9% (0.94-44%) at Day 4 and 25.6% (8-61%) at Day 28.
The early clinical data and safety profile is encouraging and
CVX-060 continues to be studied as a monotherapy and in
combination with standards of care for the treatment of solid
tumors.
¼
0.034) and Day 28 (p
¼
38.3.2 CVX-241, an Example of a Bispecific Antibody
Most diseases have complex etiology and are driven by
multiple mechanisms. It is therefore reasonable to expect
that therapeutic agents that simultaneously engage multiple
targets or pathways should offer better treatment outcomes.
Several strategies for the creation of bispecific antibodies
(BsAbs) have been proposed over the last two decades [21].
Unfortunately, most of the proposed BsAb formats suffer
from lack of product homogeneity and challenging produc-
tion problems [22]. Recent advances in antibody engineering
techniques has enabled the creation of new recombinant
formats like tandem single chain variable Fragment [23]
(scFv), diabodies [24], tandem diabodies [25], two in one
antibody [26], and dual variable domain antibodies [27]
(DVD-Ig). These new formats
solved some of
the
VEGF-binding peptide
S
S
Ac Val
1
Glu Pro Asn Cys
5
Asp Ile His Val Lys
10
Trp Val Trp Glu Cys
15
Phe Glu Arg Leu Tyr dAla dLeu
22
CONH
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
O
O
O
O
O
O
H
N
O
Cysteine branch
O
O
O
PEG
4
spacers
S
O
O
N
O
O
H
H
AZD tether
O
O
O
NH
O
O
Ac Gln
1
Lys
2
Tyr Gln Pro Leu Asp Glu Lys
9
Asp Lys
11
Thr Leu Tyr Asp Gln Phe Met Leu Gln Gln Gly
22
-
-
CH
2
ONH
2
O
O
Ang2-binding peptide
FIGURE 38.8 Structure of branched linker that connects Ang2 and VEGF binding peptides with
AZD linker.
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