Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization

Pecháň, Peter; Rubin, Hillard; Lukason, Michael; Ardinger, Jeffery; DuFresne, Elizabeth; Hauswirth, William W.; Wadsworth, Sam; Scaria, Abraham

doi:10.1038/gt.2008.115

Cited by 98 publications

(100 citation statements)

References 32 publications

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“…Intraocular VEGF levels have been found to be elevated in patients with macular degeneration and retinopathies (3). In fact, many prevailing treatments for retinal neovascularization are based on the inhibition of VEGF function (43,44). Between the two VEGF receptors, Fms-related tyrosine kinase-1 (Flt-1) and kinase insert domain receptor/fetal liver kinase-1 (KDR/Flk-1), Flk-1 (VEGFR-2) was found to be the major mediator of VEGF actions during both embryonic and pathological angiogenesis (11,13,14).…”

Section: Discussionmentioning

confidence: 99%

Activation of Cytosolic Phospholipase A2 Downstream of the Src-Phospholipase D1 (PLD1)-Protein Kinase C γ (PKCγ) Signaling Axis Is Required for Hypoxia-induced Pathological Retinal Angiogenesis

Zhang

Wang

Singh

et al. 2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Activation of Cytosolic Phospholipase A2 Downstream of the Src-Phospholipase D1 (PLD1)-Protein Kinase C γ (PKCγ) Signaling Axis Is Required for Hypoxia-induced Pathological Retinal Angiogenesis

Zhang

Wang

Singh

et al. 2011

Journal of Biological Chemistry

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“…The ability of sFLT01 protein, expressed by transfected HEK293 cells into conditioned medium, to bind and neutralize hVEGF-A was shown previously in vitro in binding and HUVEC proliferation assays (27). The in vitro binding properties of recombinant sFLT01 protein were characterized in ELISA-based assays.…”

Section: Resultsmentioning

confidence: 87%

“…CHO DXB11 cells were transfected with an expression vector containing the coding sequence of sFLT01 (27), using the Lipofectamine 2000 reagent (Invitrogen). Transfected cells were selected with increasing concentrations of methotrexate in MEM alpha-no ribonucleosides or deoxyribonucleosides (Invitrogen) containing 10% dialyzed FBS (Invitrogen).…”

Section: Sflt01 Proteinmentioning

confidence: 99%

“…27). sFLT01 has a molecular weight of approximately 80 kDa and does not contain the extracellular domain 3 of VEGFR2 as aflibercept does.…”

Section: Introductionmentioning

confidence: 99%

“…Intravitreal delivery of an AAV2 vector, encoding sFLT01 (AAV2. sFLT01), was efficacious in a gene therapy treatment of murine and nonhuman primate models of neovascularization (27,28). sFLT01 functions as a soluble decoy receptor that binds human VEGF-A (hVEGF) and human PlGF (hPlGF).…”

Section: Introductionmentioning

confidence: 99%

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sFLT01: A Novel Fusion Protein with Antiangiogenic Activity

Kurtzberg¹,

Weber²,

Nguyen³

et al. 2011

Molecular Cancer Therapeutics

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AbstractsFLT01 is a novel fusion protein that consists of the VEGF/PlGF (placental growth factor) binding domain of human VEGFR1/Flt-1 (hVEGFR1) fused to the Fc portion of human IgG 1 through a polyglycine linker. It binds to both human VEGF (hVEGF) and human PlGF (hPlGF) and to mouse VEGF (mVEGF) and mouse PlGF (mPlGF). In vitro, sFLT01 inhibited the proliferation of human umbilical vein endothelial cells and pericytes stimulated by either hVEGF or hPlGF. In vivo, sFLT01 had robust and significant antitumor activity in numerous preclinical subcutaneous tumor models including H460 non-small cell lung carcinoma, HT29 colon carcinoma, Karpas 299 lymphoma, MOLM-13 AML (acute myeloid leukemia), 786-O, and RENCA renal cell carcinoma (RCC). sFLT01 also increased median survival in the orthotopic RENCA RCC model. sFLT01 had strong antiangiogenic activity and altered intratumoral microvessel density, blood vessel lumen size and perimeter, and vascular and vessel areas in RCC models. sFLT01 treatment resulted in fewer endothelial cells and pericytes within the tumor microenvironment. sFLT01 in combination with cyclophosphamide resulted in greater inhibition of tumor growth than either agent used alone as a monotherapy in the A673 Ewing's sarcoma model. Gene expression profiling indicated that the molecular changes in the A673 sarcoma tumors are similar to changes observed under hypoxic conditions. sFLT01 is an innovative fusion protein that possessed robust antitumor and antiangiogenic activities in preclinical cancer models. It is a dual targeting agent that neutralizes both VEGF and PlGF and, therefore, has potential as a next generation antiangiogenic therapeutic for oncology. Mol Cancer Ther; 10(3); 404-15. Ó2011 AACR.

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Local acting Sticky‐trap inhibits vascular endothelial growth factor dependent pathological angiogenesis in the eye

et al. 2014

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Current therapeutic antiangiogenic biologics used for the treatment of pathological ocular angiogenesis could have serious side effects due to their interference with normal blood vessel physiology. Here, we report the generation of novel antivascular endothelial growth factor-A (VEGF) biologics, termed VEGF “Sticky-traps,” with unique properties that allow for local inhibition of angiogenesis without detectable systemic side effects. Using genetic and pharmacological approaches, we demonstrated that Sticky-traps could locally inhibit angiogenesis to at least the same extent as the original VEGF-trap that also gains whole-body access. Sticky-traps did not cause systemic effects, as shown by uncompromised wound healing and normal tracheal vessel density. Moreover, if injected intravitreally, recombinant Sticky-trap remained localized to various regions of the eye, such as the inner-limiting membrane and ciliary body, for prolonged time periods, without gaining access either to the photoreceptors/choriocapillaris area or the circulation. These unique pharmacological characteristics of Sticky-trap could allow for safe treatment of pathological angiogenesis in patients with diabetic retinopathy and retinopathy of pre-maturity.

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Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization

Cited by 98 publications

References 32 publications

Activation of Cytosolic Phospholipase A2 Downstream of the Src-Phospholipase D1 (PLD1)-Protein Kinase C γ (PKCγ) Signaling Axis Is Required for Hypoxia-induced Pathological Retinal Angiogenesis

Activation of Cytosolic Phospholipase A2 Downstream of the Src-Phospholipase D1 (PLD1)-Protein Kinase C γ (PKCγ) Signaling Axis Is Required for Hypoxia-induced Pathological Retinal Angiogenesis

sFLT01: A Novel Fusion Protein with Antiangiogenic Activity

Local acting Sticky‐trap inhibits vascular endothelial growth factor dependent pathological angiogenesis in the eye

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