Maximum Tolerated Dose of a Humanized Anti–Vascular Endothelial Growth Factor Antibody Fragment for Treating Neovascular Age-Related Macular Degeneration

Receptor tyrosine kinase inhibitors AG013764 and AG013711 reduce choroidal neovascularization in rat eye

“…Many strategies for blocking VEGF signaling in neovascular diseases have been developed, including anti-VEGF antibodies, anti-VEGF aptamer, soluble VEGF receptors or chimeric VEGF receptors, protein kinase C inhibition and VEGF receptor kinase inhibitors (Takeda et al, 2003;Barouch and Miller 2004;Liu and Regillo 2004;Kinose, Roscilli et al 2005). Several clinical trials (Gragoudas, Adamis et al 2004;Rosenfeld, Schwartz et al 2005) have demonstrated therapeutic efficacy and recently Macugen (anti-VEGF aptamer) has been approved for treating wet AMD. Macugen is injected intravitreally every six weeks and there are reports of increased complications associated with repeated injections (eight times per year) for one year (Gragoudas et al 2004), but the long term effects of repeated intravitreal injections are still unknown.…”

“…Avastin, the parent molecule of Lucentis, is a fully humanized antibody against VEGF and has recently been shown to be clinically effective against CNV (Avery et al, 2006). The results of randomized, placebo-controlled phase III studies of Lucentis (MARINA and ANCHOR) have been reported (Rosenfeld et al, 2005;Brown et al, 2006;Heier et al, 2006) and Lucentis has being approved by FDA for treating wet AMD.…”

La résistance aux traitements antiangiogéniques

“…Il cible spécifiquement un épitope du VEGF A l'empêchant d'interagir avec son récepteur, le VEGF-R2, bloquant ainsi la cascade de signalisation propre à l'angiogenèse tumorale. Le fragment F(ab')2 1 de cet anticorps, le ranibizumab (Lucentis ® ) [4], est égale-ment utilisé dans les pathologies oculaires de par sa meilleure péné-trabilité au niveau de la rétine, dans les cas de dégénérescence maculaire. Utilisé dans beaucoup de types de cancer (sein, poumon, rein, mélanome, ovaire, gastrique, lymphome) [5], le bevacizumab n'est cependant efficace dans le cas de cancers métastatiques que s'il est combiné à la chimiothérapie de référence.…”

Tratamento da forma neovascular de degeneração macular relacionada à idade com drogas antiangiogênicas

“…A injeção intravítrea de 500 microgramas de ranibizumab administrada a cada duas semanas em um modelo de MNSR induzido por laser em macacos demonstrou nenhum efeito tóxico severo e preveniu a formação de MNSR. No entanto, inflamação transitória na câmara anterior ocorreu em todos os olhos nas primeiras horas após o tratamento (38) (39) . O efeito adverso mais freqüente-mente observado nestes estudos pré-clínicos de ranibizumab foi uma perivasculite com o surgimento de anticorpos neutralizantes do fragmento Fab.…”