The Vascular Endothelial Growth Factor Trap (VEGF Trap) eye formulation*

To assess whether there is a link between estrogen, vascular endothelial growth factor (VEGF), and early aspects of uterine angiogenesis, an acute temporal study was conducted in which ovariectomized baboons were pretreated with VEGF Trap, which sequesters endogenous VEGF, and administered estradiol at time 0 h. Serum estradiol levels approximated 500 pg/ml 4–6 h after estradiol administration. VEGF mRNA levels in endometrial glandular epithelial and stromal cells were increased to values 6 h after estradiol that were 3.74 ± 0.99-fold (mean ± se) and 5.70 ± 1.60-fold greater (P < 0.05), respectively, than at 0 h. Microvessel interendothelial cell tight junctions, which control paracellular permeability, were present in the endometrium at time 0 h, but not evident 6 h after estradiol administration. Thus, microvessel paracellular cleft width increased (P < 0.01, ANOVA) from 5.03 ± 0.22 nm at 0 h to 7.27 ± 0.48 nm 6 h after estrogen. In contrast, tight junctions remained intact, and paracellular cleft widths were unaltered in estradiol/VEGF Trap and vehicle-treated animals. Endometrial microvessel endothelial cell mitosis, i.e. percent Ki67+/Ki67− immunolabeled endothelial cells, increased (P < 0.05) from 2.9 ± 0.3% at 0 h to 21.4 ± 7.0% 6 h after estrogen treatment but was unchanged in estradiol/VEGF Trap and vehicle-treated animals. In summary, the estrogen-induced disruption of endometrial microvessel endothelial tight junctions and increase in endothelial cell proliferation were prevented by VEGF Trap. Therefore, we propose that VEGF mediates the estrogen-induced increase in microvessel permeability and endothelial cell proliferation as early steps in angiogenesis in the primate endometrium.

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A novel vascular endothelial growth factor-trap KP-VR2 with enhanced ligand blocking

10.1101/2021.02.02.429416 ◽

2021 ◽

Author(s):

Mi-Ra Kim ◽

Bongkyu kim ◽

Yunsu Na ◽

Jingon Yoo ◽

Se-Ho Kim ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Binding Capacity ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Clinical Drug Development ◽

Antiangiogenic Therapies ◽

Human Igg1 ◽

Endothelial Growth Factor ◽

Vegf Trap

AbstractAntiangiogenic therapies targeting vascular endothelial growth factor (VEGF)-A have been commonly used in clinics to treat cancers over the past decade. However, their clinical efficacy has been limited, with drawbacks including the acquisition of resistance and activation of compensatory pathways resulting from elevated circulating VEGF-B and placental growth factor (PlGF) levels. Thus, we developed a novel VEGF-Trap, KP-VR2, which can neutralize VEGF-A, VEGF-B, and PlGF to mediate these problems. KP-VR2 consists of two consecutive second Ig-like domains (D2s) of VEGF receptor 1 (VEGFR-1) fused to human IgG1 Fc. KP-VR2 showed more potent decoy activity than the current VEGF-Trap against VEGF and PlGF. Most importantly, two consecutive D2s of VEGFR-1 can generate two putative binding sites, resulting in a significant improvement in binding capacity. These advances resulted in stronger antitumor efficacy in implanted tumor models than aflibercept and bevacizumab. Overall, the results of this study highlight KP-VR2 as a promising therapeutic candidate for further clinical drug development.

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Oestrogen and progesterone receptors in the marmoset endometrium: changes during the ovulatory cycle, early pregnancy and after inhibition of vascular endothelial growth factor, GnRH or ovariectomy

Reproduction ◽

10.1530/rep-06-0266 ◽

2007 ◽

Vol 134 (2) ◽

pp. 341-353 ◽

Cited By ~ 7

Author(s):

Audrey Silvestri ◽

Hamish M Fraser

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Gnrh Antagonist ◽

Vascular Endothelial ◽

Ovulatory Cycle ◽

Secretory Phase ◽

Proliferative Phase ◽

Endothelial Growth Factor ◽

Vegf Trap ◽

In Pregnancy

Marmosets are widely used, but detailed studies on localisation of endometrial oestrogen receptors α and β (ERα and ERβ ), and the progesterone receptor (PR) are lacking. These receptors were localised and semi-quantitatively analysed throughout the ovulatory cycle, weeks 2, 3 and 4 of pregnancy and after treatment with GnRH antagonist, vascular endothelial growth factor (VEGF) Trap or ovariectomy. The PR in epithelial cells increased markedly between the mid- and late proliferative phases before declining in the mid-secretory phase and pregnancy. PR in stromal cells was present throughout the cycle and levels were maintained in pregnancy. ERα was present at the mid-proliferative phase and increased in glands at the late proliferative and early secretory phases, before declining at the late secretory phase and week 4 of pregnancy. Stromal ERα showed a similar trend, but decreased earlier, by the mid-secretory phase. ERβ was highly expressed in epithelial cells throughout the cycle and in pregnancy. In stroma, increases in ERβ expression were observed at the late proliferative phase with the staining index decreasing by half as the secretory phase progressed and in pregnancy. GnRH antagonist, VEGF Trap or ovariectomy caused significant reductions in PR and ERβ expression, but not in ERα when compared with the late proliferative phase of the normal cycle. Endothelial cells expressed ERβ , but not ERα or PR. It is concluded that the steroid receptor profile in the marmoset endometrium is generally similar to the human and should provide a useful model for studies on hormonal manipulation of the endometrium.

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Phase I Study of Intravenous Vascular Endothelial Growth Factor Trap, Aflibercept, in Patients With Advanced Solid Tumors

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.9237 ◽

2010 ◽

Vol 28 (2) ◽

pp. 207-214 ◽

Cited By ~ 171

Author(s):

A. Craig Lockhart ◽

Mace L. Rothenberg ◽

Jakob Dupont ◽

Wendy Cooper ◽

Paul Chevalier ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Maximum Plasma ◽

Vascular Endothelial ◽

Dce Mri ◽

Endothelial Growth Factor ◽

Vegf Trap

Purpose Vascular endothelial growth factor (VEGF) Trap (aflibercept) is an angiogenesis inhibitor comprising portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G. This phase I study was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of VEGF Trap administered intravenously (IV) every 2 weeks. Patients and Methods Patients with refractory solid tumors or non-Hodgkin's lymphoma with adequate organ function were eligible. Pharmacokinetic/pharmacodynamic markers included measurement of plasma VEGF bound to VEGF Trap and free VEGF Trap. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was incorporated to measure the biologic effects of the drug on tumor vascularity and permeability. Results The study enrolled 47 patients at doses ranging from 0.3 to 7.0 mg/kg IV every 2 weeks. Dose-limiting toxicities were rectal ulceration and proteinuria at the 7.0 mg/kg dose. Other mechanism-specific toxicities included hypertension. On the basis of these observations and on pharmacokinetics, the recommended phase II dose of VEGF Trap as a single agent is 4 mg/kg every 2 weeks. Three RECIST (Response Evaluation Criteria in Solid Tumors) –defined partial responses were observed, one at the 3.0 mg/kg and two at the 7.0 mg/kg dose level. Maximum plasma concentration of free VEGF Trap increased proportionally with dose. Maximal VEGF-bound VEGF Trap complex levels were reached at doses ≥ 2.0 mg/kg. Changes in volume transfer constant measured by DCE-MRI at baseline and at 24 hours after administration indicate a possible dose-related change in this pharmacodynamic marker. Conclusion IV VEGF Trap was well tolerated at the dose levels tested. Pharmacodynamic and pharmacokinetic markers were indicative of VEGF blockade.

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