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[Abstract]

Monobodies are binding scaffold proteins originating from a human fibronectin domain III (Fn3) scaffold that can be easily engineered with specificity and affinity. Human EphA2 (hEphA2) is an early detection marker protein for various tumors including lung, breast, and colon cancer. In this study, we isolated two hEphA2-specific monobodies (E1 and E10) by screening a yeast surface display library. They showed the same amino acid sequence except in the DE loop and had high affinity (~2 nM Kd) against hEphA2. E1 bound only hEphA2 and mEphA2, although it bound hEphA2 with an affinity 2-fold higher than that of mEphA2. However, E10 also bound the mEphA6 and mEphA8 homologs as well as hEphA2 and mEphA2. Thus, E1 but not E10 was highly specific for hEphA2. E1 specifically bound human cells and xenograft tumor tissues expressing hEphA on the cell surface. In vivo optical imaging showed strong targeting of Cy5.5-labeled E1 to mouse tumor tissue induced by PC3 cells, a human prostate cancer cell line that expresses a high level of hEphA2. In conclusion, the highly specific monobody E1 is useful as a hEphA2 probe candidate for in vivo diagnosis and therapy. 

[Author Information]

Park SH1, Park S2, Kim DY1, Pyo A1, Kimura RH3, Sathirachinda A3, Choy HE2, Min JJ1, Gambhir SS3, Hong Y2.

1Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.

2Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.

3Molecular Imaging Program at Stanford, Department of Radiology, Bio-X Program, Stanford University, Palo Alto, CA, United States of America.