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A novel engineered VEGF blocker with an excellent pharmacokinetic profile and
robust anti-tumor activity
#MMPMID25881012
Liu L
; Yu H
; Huang X
; Tan H
; Li S
; Luo Y
; Zhang L
; Jiang S
; Jia H
; Xiong Y
; Zhang R
; Huang Y
; Chu CC
; Tian W
BMC Cancer
2015[Mar]; 15
(?): 170
PMID25881012
show ga
BACKGROUND: Relatively poor penetration and retention in tumor tissue has been
documented for large molecule drugs including therapeutic antibodies and
recombinant immunoglobulin constant region (Fc)-fusion proteins due to their
large size, positive charge, and strong target binding affinity. Therefore, when
designing a large molecular drug candidate, smaller size, neutral charge, and
optimal affinity should be considered. METHODS: We engineered a recombinant
protein by molecular engineering the second domain of VEGFR1 and a few flanking
residues fused with the Fc fragment of human IgG1, which we named HB-002.1. This
recombinant protein was extensively characterized both in vitro and in vivo for
its target-binding and target-blocking activities, pharmacokinetic profile,
angiogenesis inhibition activity, and anti-tumor therapeutic efficacy. RESULTS:
HB-002.1 has a molecular weight of ~80 kDa, isoelectric point of ~6.7, and an
optimal target binding affinity of <1 nM. The pharmacokinetic profile was
excellent with a half-life of 5 days, maximal concentration of 20.27 ?g/ml, and
area under the curve of 81.46 ?g·days/ml. When tested in a transgenic zebrafish
embryonic angiogenesis model, dramatic inhibition in angiogenesis was exhibited
by a markedly reduced number of subintestinal vessels. When tested for anti-tumor
efficacy, HB-002.1 was confirmed in two xenograft tumor models (A549 and
Colo-205) to have a robust tumor killing activity, showing a percentage of
inhibition over 90% at the dose of 20 mg/kg. Most promisingly, HB-002.1 showed a
superior therapeutic efficacy compared to bevacizumab in the A549 xenograft model
(tumor inhibition: 84.7% for HB-002.1 versus 67.6% for bevacizumab, P<0.0001).
CONCLUSIONS: HB-002.1 is a strong angiogenesis inhibitor that has the potential
to be a novel promising drug for angiogenesis-related diseases such as tumor
neoplasms and age-related macular degeneration.
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