TY - JOUR
T1 - Synthesis and characterization of a high-affinity α vβ 6-specific ligand for in vitro and in vivo applications
AU - Li, Shunzi
AU - McGuire, Michael J.
AU - Lin, Mai
AU - Liu, Ying Horng
AU - Oyama, Tsukasa
AU - Sun, Xiankai
AU - Brown, Kathlynn C.
PY - 2009/5/1
Y1 - 2009/5/1
N2 - The α vβ 6 integrin is an attractive therapeutic target for several cancers due to its role in metastasis and its negligible expression in normal tissues. We previously identified a peptide from a phage-displayed peptide library that binds specifically to α vβ 6. The tetrameric version of the peptide has higher affinity for its cellular targets than the corresponding monomers. However, the inefficient synthesis limits its clinical potential. We report here a convergent synthesis producing the tetrameric peptide in high yield and purity. The ease of the synthesis allows for rapid optimization of the peptide. We have optimized this α vβ 6 integrin-binding peptide, determining the minimal binding domain and valency. Importantly, the half-maximal binding affinity of the optimal peptide for its target cell is in the 40 to 60 pmol/L range, rivaling the affinity of commonly used antibody-targeting reagents. This peptide mediates cell-specific uptake, is functional in diagnostic formats, is stable in sera, and can home to a tumor in an animal. We anticipate that this high-affinity ligand for α vβ 6 will find clinical use as a diagnostic and therapeutic reagent.
AB - The α vβ 6 integrin is an attractive therapeutic target for several cancers due to its role in metastasis and its negligible expression in normal tissues. We previously identified a peptide from a phage-displayed peptide library that binds specifically to α vβ 6. The tetrameric version of the peptide has higher affinity for its cellular targets than the corresponding monomers. However, the inefficient synthesis limits its clinical potential. We report here a convergent synthesis producing the tetrameric peptide in high yield and purity. The ease of the synthesis allows for rapid optimization of the peptide. We have optimized this α vβ 6 integrin-binding peptide, determining the minimal binding domain and valency. Importantly, the half-maximal binding affinity of the optimal peptide for its target cell is in the 40 to 60 pmol/L range, rivaling the affinity of commonly used antibody-targeting reagents. This peptide mediates cell-specific uptake, is functional in diagnostic formats, is stable in sera, and can home to a tumor in an animal. We anticipate that this high-affinity ligand for α vβ 6 will find clinical use as a diagnostic and therapeutic reagent.
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U2 - 10.1158/1535-7163.MCT-08-1098
DO - 10.1158/1535-7163.MCT-08-1098
M3 - Article
C2 - 19435868
AN - SCOPUS:66849093525
SN - 1535-7163
VL - 8
SP - 1239
EP - 1249
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 5
ER -