Small-animal PET of tumor angiogenesis using a (76)Br-labeled human recombinant antibody fragment to the ED-B domain of fibronectin.
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 (76)Br 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 (76)Br using bromoperoxidase/H(2)O(2). 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. (76)Br-L19-SIP stability in mouse serum proved to be similar to that of the (125)I-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 (76)Br-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.


CONCLUSIONS
(76)Br-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.
Rossin
Raffaella
R
Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Berndorff
Dietmar
D
Friebe
Matthias
M
Dinkelborg
Ludger M
LM
Welch
Michael J
MJ
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001967:Bromine Radioisotopes / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000906:Antibodies; D001967:Bromine Radioisotopes; D005353:Fibronectins; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins