The potential of the HER2-targeting antibody trastuzumab as a 
radioimmunoconjugate useful for both imaging and therapy was investigated. 
Conjugation of trastuzumab with the acyclic bifunctional chelator CHX-A"-DTPA 
yielded a chelate:protein ratio of 3.4 ± 0.3; the immunoreactivity of the 
antibody unaffected. Radiolabeling was efficient, routinely yielding a product 
with high specific activity. Tumor targeting was evaluated in mice bearing 
subcutaneous (s.c.) xenografts of colorectal, pancreatic, ovarian, and prostate 
carcinomas. High uptake of the radioimmunoconjugate, injected intravenously 
(i.v.), was observed in each of the models, and the highest tumor %ID/g (51.18 ± 
13.58) was obtained with the ovarian (SKOV-3) tumor xenograft. Specificity was 
demonstrated by the absence of uptake of 111In-trastuzumab by melanoma (A375) 
s.c. xenografts and 111In-HuIgG by s.c. LS-174T xenografts. Minimal uptake of 
i.v. injected 111In-trastuzumab in normal organs was confirmed in 
non-tumor-bearing mice. The in vivo behavior of 111In-trastuzumab in mice 
bearing intraperitoneal (i.p.) LS-174T tumors resulted in a tumor %ID/g of 
130.85 ± 273.34 at 24 h. Visualization of tumor, s.c. and i.p. xenografts, was 
achieved by γ-scintigraphy and PET imaging. Blood pool was evident as expected, 
but cleared over time. The blood pharmacokinetics of i.v. and i.p. injected 
111In-trastuzumab was determined in mice with and without tumors. The data from 
these in vitro and in vivo studies supported advancement of radiolabeled 
trastuzumab into two clinical studies, a Phase 0 imaging study in the Molecular 
Imaging Program of the National Cancer Institute and a Phase 1 
radioimmunotherapy study at the University of Alabama.