title: Axitinib inhibits retinal and choroidal neovascularization in in vitro and in vivo models.
abstract: Age-related Macular Degeneration (AMD) is the leading cause of visual impairment and blindness in the elderly in developed countries. Neovascular/exudative (wet) AMD is the aggressive form of AMD and can involve choroidal neovascularization and vascular leakage. Anti-vascular endothelial growth factor (anti-VEGF) medications have significantly improved treatment of wet-AMD. However, only approximately 40% of patients obtain full benefit from anti-VEGF therapy and the medications are given by intravitreal injection. Axitinib, a small molecule multi-receptor tyrosine kinase inhibitor used for the treatment of advanced renal cell carcinoma, is taken orally and inhibits VEGF activity by blocking VEGF receptors. Axitinib also has the advantage of blocking platelet derived growth factor (PDGF) receptors which play a role in neovascularization. Using in vitro human retinal microvascular endothelial cells (HRMVECs), human brain vascular pericytes (HBVRs), 3D co-culture vessel sprout assay, and in vivo laser induced rat choroidal neovascularization (CNV) models, the effect of axitinib on neovascularization was evaluated. Axitinib inhibited neovascularization better than anti-VEGF and/or anti-hPDGF-B mAb in the in vitro models demonstrating that combined inhibition of both VEGF and PDGF pathways may be synergistic in treating wet-AMD. Additionally, axitinib showed good efficacy at a low dose (0.875 mg/day) in laser-induced CNV model in rats. In conclusion our data shows that axitinib, an inhibitor of VEGF and PDGF-B pathways may be useful in ameliorating wet-AMD therapy.
authors.affiliation: Global Science and Technology-WCM, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA. Electronic address: anand.giddabasappa@pfizer.com.
authors.forename: Anand
authors.initials: A
authors.lastname: Giddabasappa
authors.affiliation: Global Science and Technology-WCM, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Kush
authors.initials: K
authors.lastname: Lalwani
authors.affiliation: Global Science and Technology-WCM, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Rand
authors.initials: R
authors.lastname: Norberg
authors.affiliation: Pharmaceutical Sciences, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Hovhannes J
authors.initials: HJ
authors.lastname: Gukasyan
authors.affiliation: Global Science and Technology-WCM, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: David
authors.initials: D
authors.lastname: Paterson
authors.affiliation: Global Clinical Affairs, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Schachar
authors.affiliation: External R&D Innovation, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Kay
authors.initials: K
authors.lastname: Rittenhouse
authors.affiliation: Oncology Clinical Development, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Klamerus
authors.affiliation: Global Biotherapeutics Technologies, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Lydia
authors.initials: L
authors.lastname: Mosyak
authors.affiliation: Global Science and Technology-WCM, Pfizer Inc., 10724 Science Center Drive, San Diego, CA 92121, USA. Electronic address: jeetendra.eswaraka@pfizer.com.
authors.forename: Jeetendra
authors.initials: J
authors.lastname: Eswaraka
mesh_terms: D000368:Aged; D000818:Animals; D000077784:Axitinib; D049109:Cell Proliferation / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects; D005451:Fluorescein Angiography; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology / Q000627:therapeutic use*; D058449:Intravitreal Injections; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D020286:Pericytes / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib
keywords: 3D co-culture model; Axitinib; In vitro angiogenesis; Rat choroidal neovascularization; Small molecule receptor tyrosine kinase inhibitor; Wet age-related macular degeneration