Tokyo University of Agriculture Repository / 東京農業大学リポジトリ
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Spatial and economic quantification of provisioning service by eelgrass beds in Lake Notoro, Hokkaido, Japan
Get PDF能取湖（網走市）のアマモ場の空間構造を音響手法を用いて明らかにし、その構造とホッカイエビ（北海しまえび）の現存量との関係から、アマモ場の生態系サービス（供給サービス）を推算した
Annexin A1‐Targeted D‐Peptide‐Monomethyl Auristatin E Conjugate Enhanced Antitumor Effect of Monomethyl Auristatin E for Chemotherapy of Prostate Cancer
Get PDFBackground: N‐terminus 15 amino acid (MC16) of Annexin A1 (ANXA1) is an effective therapeutic target for tumors and
tumor vasculature as it specifically localizes to the cell surface of tumor cells and tumor vascular endothelial cells. We identified
the D‐type peptide (hpnevrs, dhp7) by mirror‐image phage display targeting L‐type MC16 and tested the hypothesis that
intravenously injected c(vcMMAE)dhp7 eradicates prostate tumor in mice with less adverse side effects than that of mc‐Val‐Cit‐
PAB‐monomethyl auristatin (vcMMAE) alone.
Methods: The binding affinity of dhp7 to MC16 of ANXA1 was analyzed by biolayer interferometry and in silico conformational
analysis. c(vcMMAE)dhp7 was synthesized by coupling dhp7 to vcMMAE to evaluate the antitumor effects. A subcutaneous
tumor model was generated by inoculating the luciferase‐expressing prostate cancer PC‐3 cell line, PC‐3‐hLuc‐PSMA,
into the nude mice. 1.25 mg/kg vcMMAE or 2.14 mg/kg c(vcMMAE)dhp7, the equal dose as 1.25 mg/kg vcMMAE, was administered
intravenously every 3 or 4 days and growth of tumors was assessed by photon count using an IVIS system.
Results: The dhp7 bound specifically to L‐type MC16 (KD 0.48 μM) but not bound to D‐type MC16 and mutant L‐type MC16.
Both in vitro and in silico interaction analysis indicating the α‐helix of the L‐type MC16 may be important for dhp7 binding.
Fluorescence labeled‐dhp7 accumulated in both ANXA1 positive cells and subcutaneous prostate tumor. To evaluate the
antitumor effect, c(vcMMAE)dhp7 was synthesized by coupling dhp7 with mc‐Val‐Cit‐PAB‐monomethyl auristatin E
(vcMMAE) as a payload. The IC50 s of vcMMAE (129.9 ng) and c(vcMMAE)dhp7 (122.7 ng) against prostate cancer cells
showed almost equivalent in vitro drug sensitivity. The c(vcMMAE)dhp7‐treated mice showed significant antitumor effects
including complete responses at the same dose of MMAE (1.25 mg/kg) as mice treated with vcMMAE alone. Pathological
analysis of the residual tumor showed that CD31 density of the c(vcMMAE)dhp7 treated group was significantly higher than that of the vcMMAE group, and the Ki‐67 index was significantly lower than that of the vcMMAE alone. Clinical chemistry tests
showed side effects of MMAE significantly improved in terms of hepatic/biliary toxicity in c(vcMMAE)dhp7‐treated group.
Conclusions: The c(vcMMAE)dhp7 conjugate exerts a better antitumor effect than vcMMAE on ANXA1‐positive prostate
cancer