Anti-FIGF monoclonal antibody, clone 39BU854.399.59

Purpose: Intravitreal antievascular endothelial growth factor (VEGF) injections are currently the standard treatment for neovascular age-related macular degeneration (AMD), but a broad range of response rates has been observed. We evaluated the association of single nucleotide polymorphisms (SNPs) in VEGF genes and their receptors (VEGFR) with the response rate to ranibizumab in 366 patients with neovascular AMD. Design: Case series study. Participants: A total of 366 eyes of 366 patients with neovascular AMD. Methods: Visual acuity (VA) was determined at baseline, after 3 monthly ranibizumab injections, and after 1 year of treatment. Genotyping of 126 SNPs in the genes encoding VEGF family members VEGFA, VEGFB, VEGFC, VEGFD (FIGF), and placental growth factor (PGF); VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4); and the gene encoding pigment epithelium-derived factor (PEDF) (SERPINF1) was performed. Main Outcome Measures: The changes in VA after 3 injections and after 1 year of treatment and their association with VEGF and VEGFR genotypes. Results: Univariate analyses of variance (ANOVAs) revealed a significant effect of SNP rs4576072 in the VEGFR2 gene on VA change after 12 months (F[1,235] = 14.05; P = 0.02). A stepwise linear regression analysis returned a model (P = 0.01) with SNPs rs4576072 and rs6828477 in the VEGFR2 gene as independent predictors for VA change after 12 months, with a mean increase in VA of 0.26 on the logarithm of the minimum angle of resolution (logMAR) scale in patients with 3 contributing minor alleles compared with a loss of 0.03 logMAR in patients with no minor allele. Conclusions: Polymorphisms in the VEGFR2/KDR gene significantly influence visual outcome in patients receiving ranibizumab treatment for neovascular AMD. This study shows that genetic variation partially explains the wide range of response to ranibizumab treatment, which in the future might help clinicians tailoring medical interventions to individual needs. Ophthalmology 2014;121:905-910 (C) 2014 by the American Academy of Ophthalmology.

Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.