Optimizing dosage regimen for FP3 based on vascular normalization window monitored by ratio of Ang-1 to Ang-2

Vascular normalization explained the successful efficacy of combined antiangiogenic and cytotoxic therapy. The optimal dosage regimen of anti-VEGF therapy to achieve a maximized efficacy and a minimized toxicity response needs further investigations based on vascular normalization monitoring. FP3 (also referred to as Conbercept, KH902 or Fusion protein III, developed by KanghongBiotechnology, China) is a novel anti-VEGF agent, which has been demonstrated to have a stable effect on antiangiogenesis as well as on vascular normalization. A patient-derived colorectal cancer xenograft model was established. Dose-escalation study of FP3 (7.5, 15, 30 and 60 mg/kg) combined with CPT-11 was performed to discover the optimal dosage regimen. Serum Ang-1 and Ang-2 expression were detected by ELISA. A potential correlation between drug responses and Ang-1/Ang-2 ratio were analyzed. The PDX model was evaluated as FP3-sensitive. FP3 (15 mg/kg, i.v.qw) combined with CPT-11 was found to be the optimal dosage regimen. All dosages of FP3 groups showed an ascending Ang1/Ang2 ratio after drug administration, while ascending velocity was less significant in 7.5 and 15 mg/kg FP3 groups than that in 30 and 60 mg/kg FP3 groups. The Ang1/Ang2 ratio was shown somewhat higher in 15 mg/kg FP3 compared with that in 7.5 mg/kg FP3 group despite of no statistical significance. In our study, the optimal dosage regimen for FP3 in combination with CPT-11 was discovered. The ratio of Ang-1/Ang-2 was demonstrated as an effective surrogate maker for vascular normalization, although further confirmations are needed.