Dual VEGF and PDGF Antagonists to Treat Exudative AMD
Dual inhibition of VEGF and PDGF has been an important treatment strategy for numerous diseases. As of 2007, there were over 15 therapies in use or in development that involved combined inhibition of VEGF and PDGF. Some of these agents, such as sorafenib, have been validated in major clinical trials. Broadly, VEGF and PDGF inhibitors fall into two categories: small molecule inhibitors of the active kinase domains of VEGF and PDGF receptors (VEGFR, PDGFR) and biologic agents (e.g., antibodies, aptamers and decoy receptors) that bind directly to VEGF or PDGF and prevent ligation with their cognate receptors. Due to similarities in the kinase domains of VEGFR and PDGFR, many small molecule inhibitors have some degree of cross-inhibition between these receptors. By contrast, biologic agents tend to have high affinity and specificity for the individual VEGF and PDGF peptides; thus cross-reactivity between targets does not occur and two separate biologic agents are required to simultaneously target both VEGF and PDGF pathways.
The benefit of dual VEGF/PDGF therapy has been demonstrated in animal models of ocular disease using small molecules and antibody-derivatives targeting VEGF and PDGF (Table 1). Jo et al. conducted one of the first preclinical studies examining VEGF and PDGF inhibition in a laser-induced CNV model in mice. In this study, it was shown that combined administration of anti-VEGF and anti-PDGF aptamers was superior to anti-VEGF therapy alone for both prevention and treatment of laser-induced CNV.
Preclinical studies have also examined the use of multi-kinase small molecule inhibitors, such as sunitinib and pazopanib, in models of pathologic ocular neovascularization. Sunitinib is a small molecule receptor tyrosine kinase inhibitor that prevents phosphorylation of VEGFR2 and PDGFR-β in vivo and is approved for use in the treatment of renal and gastrointestinal cancers. In 2010, Perez-Santonja et al. reported that administration of sunitinib is more effective than bevacizumab at reducing corneal neovascularization in a suture-induced corneal neovascularization model in rabbits. Sunitinib reduced corneal neovascularization 83.3% in comparison with a reduction of 28.5% with bevacizumab.
Pazopanib is a small molecule inhibitor of VEGFR, PDGFR and c-Kit that is approved for the treatment of renal cell carcinoma and certain types of soft tissue sarcoma. In 2009, Takahashi et al. reported that pazopanib reduces neovascularization in mice with laser-induced CNV. In this study, mice were administered drug or vehicle by gavage or injection for 7 days. Twice-daily administration of 100 mg/kg pazopanib by gavage resulted in a 71% reduction in CNV while once-daily administration of 100 μg pazopanib by injection resulted in a 40% reduction in CNV.
Together, these preclinical data indicate that both antibody and small kinase-based VEGF/PDGF antagonists are effective in animal models of pathologic ocular neovascularization and that combined VEGF/PDGF inhibition is more effective than VEGF inhibition alone.
Preclinical Data Supporting the Use of Dual VEGF/PDGF Antagonism in the Treatment of Wet AMD
Dual inhibition of VEGF and PDGF has been an important treatment strategy for numerous diseases. As of 2007, there were over 15 therapies in use or in development that involved combined inhibition of VEGF and PDGF. Some of these agents, such as sorafenib, have been validated in major clinical trials. Broadly, VEGF and PDGF inhibitors fall into two categories: small molecule inhibitors of the active kinase domains of VEGF and PDGF receptors (VEGFR, PDGFR) and biologic agents (e.g., antibodies, aptamers and decoy receptors) that bind directly to VEGF or PDGF and prevent ligation with their cognate receptors. Due to similarities in the kinase domains of VEGFR and PDGFR, many small molecule inhibitors have some degree of cross-inhibition between these receptors. By contrast, biologic agents tend to have high affinity and specificity for the individual VEGF and PDGF peptides; thus cross-reactivity between targets does not occur and two separate biologic agents are required to simultaneously target both VEGF and PDGF pathways.
The benefit of dual VEGF/PDGF therapy has been demonstrated in animal models of ocular disease using small molecules and antibody-derivatives targeting VEGF and PDGF (Table 1). Jo et al. conducted one of the first preclinical studies examining VEGF and PDGF inhibition in a laser-induced CNV model in mice. In this study, it was shown that combined administration of anti-VEGF and anti-PDGF aptamers was superior to anti-VEGF therapy alone for both prevention and treatment of laser-induced CNV.
Preclinical studies have also examined the use of multi-kinase small molecule inhibitors, such as sunitinib and pazopanib, in models of pathologic ocular neovascularization. Sunitinib is a small molecule receptor tyrosine kinase inhibitor that prevents phosphorylation of VEGFR2 and PDGFR-β in vivo and is approved for use in the treatment of renal and gastrointestinal cancers. In 2010, Perez-Santonja et al. reported that administration of sunitinib is more effective than bevacizumab at reducing corneal neovascularization in a suture-induced corneal neovascularization model in rabbits. Sunitinib reduced corneal neovascularization 83.3% in comparison with a reduction of 28.5% with bevacizumab.
Pazopanib is a small molecule inhibitor of VEGFR, PDGFR and c-Kit that is approved for the treatment of renal cell carcinoma and certain types of soft tissue sarcoma. In 2009, Takahashi et al. reported that pazopanib reduces neovascularization in mice with laser-induced CNV. In this study, mice were administered drug or vehicle by gavage or injection for 7 days. Twice-daily administration of 100 mg/kg pazopanib by gavage resulted in a 71% reduction in CNV while once-daily administration of 100 μg pazopanib by injection resulted in a 40% reduction in CNV.
Together, these preclinical data indicate that both antibody and small kinase-based VEGF/PDGF antagonists are effective in animal models of pathologic ocular neovascularization and that combined VEGF/PDGF inhibition is more effective than VEGF inhibition alone.
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