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Small-Animal PET of Tumor Angiogenesis Using a ⁷⁶Br-Labeled Human Recombinant Antibody Fragment to the ED-B Domain of Fibronectin

¹ Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri; and ² Bayer Schering Pharma, Global Drug Discovery, Berlin, Germany

Correspondence: For correspondence or reprints contact: Michael J. Welch, PhD, Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., Campus Box 8225, St. Louis, MO 63110. E-mail: welchm{at}wustl.edu

The aim of this study was to image the extra domain B (ED-B) of fibronectin, an angiogenesis-related target, in solid tumors using small-animal PET. Toward this aim, an ED-B fibronectin-binding human antibody derivative (L19-SIP) was labeled with ⁷⁶Br via an enzymatic approach. Biodistribution and imaging studies were performed in human teratoma–bearing mice for up to 48 h after injection. Methods: L19-SIP was labeled with ⁷⁶Br using bromoperoxidase/H₂O₂. The stability of the labeled antibody was tested both in vitro and in vivo. Biodistribution and small-animal imaging studies (PET and CT) were performed in F9-bearing 129/sv mice (n = 3 or 4). Results: The enzymatic radiobromination approach afforded the labeled antibody in high yield (>55%) under mild reaction conditions. ⁷⁶Br-L19-SIP stability in mouse serum proved to be similar to that of the ¹²⁵I-labeled analog (>80% of intact material at 48 h after injection). Fast and specific in vivo targeting was obtained in tumors and other organs expressing ED-B fibronectin (i.e., ovaries and uterus). However, slow renal clearance and persistent activity predominately in blood and stomach suggests partial ⁷⁶Br-L19-SIP debromination in vivo. This debromination was confirmed in a metabolism study in normal mice. The F9 tumors were clearly imaged by small-animal PET at each considered time point, starting at 5 h up to 48 h after injection. Conclusion: ⁷⁶Br-L19-SIP specifically accumulated at the target site, enabling detailed small-animal PET of tumor neovasculature. Therefore, targeting the angiogenesis-associated expression of ED-B fibronectin can be a valuable tool for tumor detection using molecular imaging with PET.

Key Words: angiogenesis • ED-B • fibronectin • L19-SIP • ⁷⁶Br • PET

COPYRIGHT © 2007 by the Society of Nuclear Medicine, Inc.

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