Biomedical Engineering Reference
In-Depth Information
TABLE 38.1
Influence of Tether Position the Bioactivity and PK Profile of Ang2 Targeting CovX-Bodies
Compound#
Sequence
IC
50
(nM)
T
1/2
(h)
Peptide 1
QK(Ac)YQPLDELDK(Ac)TLYDQFMLQQG
98
0.1
1
K(0P)K(Ac)YQPLDELDK(Ac)TLYDQFMLQQG
1.8
24
2
QK(0P)YQPLDELDK(Ac)TLYDQFMLQQG
0.3
13
3
QK(Ac)K(0P)QPLDELDK(Ac)TLYDQFMLQQG
0.2
18
4
QK(Ac)YK(0P)PLDELDK(Ac)TLYDQFMLQQG
>
1000
ND
5
QK(Ac)YQK(0P)LDELDK(Ac)TLYDQFMLQQG
44.2
ND
6
QK(Ac)YQPK(0P)DELDK(Ac)TLYDQFMLQQG
>
1000
ND
7
QK(Ac)YQPLK(0P)ELDK(Ac)TLYDQFMLQQG
>
1000
ND
8
QK(Ac)YQPLDK(0P)LDK(Ac)TLYDQFMLQQG
0.3
35
9
QK(Ac)YQPLDEK(0P)DK(Ac)TLYDQFMLQQG
2.0
72
10
QK(Ac)YQPLDELK(0P)K(Ac)TLYDQFMLQQG
>
1000
ND
CVX-32
QK(Ac)YQPLDELDK(0P)TLYDQFMLQQG
0.3
74
12
QK(Ac)YQPLDELDK(Ac)K(0P)LYDQFMLQQG
0.1
56
13
QK(Ac)YQPLDELDK(Ac)TK(0P)YDQFMLQQG
>
1000
ND
14
QK(Ac)YQPLDELDK(Ac)TLK(0P)DQFMLQQG
32.8
ND
15
QK(Ac)YQPLDELDK(Ac)TLYK(0P)QFMLQQG
0.2
66
16
QK(Ac)YQPLDELDK(Ac)TLYDK(0P)FMLQQG
0.3
94
17
QK(Ac)YQPLDELDK(Ac)TLYDQK(0P)MLQQG
19.5
ND
18
QK(Ac)YQPLDELDK(Ac)TLYDQFK(0P)LQQG
0.6
72
19
QK(Ac)YQPLDELDK(Ac)TLYDQFMK(0P)QQG
0.1
65
20
QK(Ac)YQPLDELDK(Ac)TLYDQFMLK(0P)QG
0.1
35
21
QK(Ac)YQPLDELDK(Ac)TLYDQFMLQK(0P)G
0.3
27
22
QK(Ac)YQPLDELDK(Ac)TLYDQFMLQQK(0P)
0.2
20
CVX-060
QK(Ac)YQPLDEK(Ac)DK(0P)TLYDQFMLQQG
0.5
110
CVX-060T
QK(Ac)YQPLDEK(Ac)DK(0P)TLYDQFMLQQG
342
ND
CVX-87
QK(Ac)YQPLDELDK(0P)TLFDQFMLQQG
0.2
61
Peptide 2
TNFMPMDDLEQRLYEQFILQQG
5.4
ND
CVX-37
(DFB)TNFMPMDDLEK(0P)RLYEQFILQQG
0.4
26
CVX-51
(0P)TNFMPMDDLEQRLYEQFILQQG
1.8
28
The in vitro potency of CovX-Bodies tethered at different residues, indicated by K(0P), in blocking Ang2-Tie2 interaction and their mouse pharmacokinetics.
ND, not determined; 0P, no PEG unit between peptide and the AZD linker; K(Ac), acetylated Lysine; DFB, 1,5-difluorobenzoyl. Compounds 1-10, 12-22,
CVX-32, CVX-060, CVX-87, CVX-37, and CVX-51 were all tested as CovX-Bodies, while peptides 1, 2, and CVX-060T (the pharmacophores of CVX-060)
were also tested as controls. The IC
50
s were average data from at least three independent preparations for each compound.
Additionally, the intratumoral levels of proangiogenic Tie2
þ
CD11b
þ
cells were reduced (by up to 85%) after treatment
with CVX-060, demonstrating for the first time that selective
Ang-2 targeting can block the recruitment of proangiogenic
monocytes into tumors. CVX-060 demonstrated significant
additive efficacy in xenograft models when combined with
standard of care agents such as sunitinib, sorafenib, bev-
acizumab, irinotecan, and docetaxel. This demonstrates that
CVX-060 is effective at reducing tumor angiogenesis and
growth when administrated alone or in combination with
standard of care agents.
The safety and efficacy of CVX-060 are currently being
evaluated in patients with advanced solid tumors [19]. On
the basis of the available datasets from 30 of 34 patients who
were enrolled in an early Phase I study, CVX-060 was
generally well tolerated in patients and a maximum tolerated
dose (MTD) was not reached during trial. The preliminary
pharmacokinetic analysis suggests dose proportional
increases in area under the curve (AUC) and mean with
mean
at internal sites showed better half-lives compared with the
ones tethered near either termini. Thus, CovX-Body with an
internal tether at position 11 was found to have optimal
potency and pharmacokinetic profile. To improve its potency
and pharmacokinetic profile, the peptide pharmacophore
was subjected to a series of point mutations with natural
and unnatural amino acids including several non-natural
capping groups at the N-terminus. Thus, when Lys at posi-
tion 9 was changed to acetyl Lys, the resulting CovX-Body,
CVX-060 had a significantly improved half-life of 110 h in
mice. As shown in Table 38.1, CovXing the lead peptide
dramatically improves its potency and half-life, thus making
it a viable development candidate. CVX-060 selectively
binds Ang2 (Kd: 1.89
10
10
M; k
off
: 5.69
10
5
s
1
)
blocks the Ang2/Tie-2 interactions and does not interact
with Ang1, Ang3, or Ang4. In staged Colo-205 xenograft
models, the animals treated with CVX-060 (10mg/kg, once
a week), had a significant tumor growth inhibition (38-60%)
coupled with reduction in intratumoral Ang2 protein levels
(
50%) and reduction in microvessel density (34-48%).
half-life 5.5 days. The most common adverse events
Search WWH ::
Custom Search