Targeting of HER2 Antigen for the Treatment of Disseminated Peritoneal Disease

Abstract

The studies reported herein demonstrate the efficacy of ␣-particle-targeted radiation therapy of peritoneal disease with Herceptin as the targeting vehicle. Using the CHX-A-DTPA linker, Herceptin was radiolabeled with indium-111 and bismuth-213 with high efficiency without compromising immunoreactivity. A pilot radioimmunotherapy study treating mice bearing 5-day LS-174T (i.p.) xenografts, a low but uniform HER2 expressing, human colon carcinoma, with a single dose of 213 Bi-CHX-A"-Herceptin, proved disappointing. This defined the effect of tumor burden/size on tumor response to radioimmunotherapy with ␣-radiation. A more successful experiment with a lower tumor burden (3 days) in mice followed. A specific dose-response (P ‫؍‬ 0.009) was observed, and although a maximum-tolerated dose was not determined, a dose of 500 to 750 Ci was selected as the operating dose for future experiments based on changes in animal weight. Median survival was increased from 20.5 days for the mock-treated mice to 43 and 59 days with 500 and 750 Ci, respectively. The therapeutic effectiveness of 213 Bi-CHX-A"-Herceptin was also evaluated in a second animal model for peritoneal disease with a human pancreatic carcinoma (Shaw). The results of this study were not as dramatic as with the former model, and higher doses were required to obtain an increase in survival of the mice (P ‫؍‬ 0.001).

Development and Characterization of Clinical-Grade 89Zr-Trastuzumab for HER2/neu ImmunoPET Imaging

“…Similar to what we observed in the present study, tumor uptake of ICR12 was not influenced by the protein dose, but the T/B ratio decreased with an increasing amount of protein (30). With the murine predecessor of trastuzumab (4D5), maximal tumor uptake was 35% (31,32), comparable to what we found. 89 Zr is a relatively new, yet promising, long-lived PET isotope.…”

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

“…tumors by 3-to 4-fold. 1,2 This therapeutic benefit can be potentiated by incorporating chemotherapeutics such as gemcitabine, paclitaxel or carboplatin into the treatment regimen. 3-5 213 Bismuth, a decay product of 225 Ac, has a T 1/2 of 45.7 min whereas 212 Pb is a 10.6 h half-life b ¡ -emitter that decays to 212 Bi, an a-emitter with a T 1/2 of 60.6 min.…”

Pre-clinical evaluation of [111In]-benzyl-DOTA-ZHER2:342, a potential agent for imaging of HER2 expression in malignant tumors

“…According to Milenic and co-authors (32,33), this cell line possesses low but uniform expression of HER2 and may be a good model to demonstrate the sensitivity of Z HER2:342 in detection of lowlevel antigen expression. Female outbred Balb/c nu/nu mice were sc injected with one million LS174T cells in the hind leg 3 weeks before the experiment.…”