Treatment of patients with
human epidermal growth factor receptor 2 (HER2)-expressing
tumors using the
monoclonal antibody trastuzumab increases survival. The Affibody-based
peptide nucleic acid (PNA)-mediated pretargeted
radionuclide therapy has demonstrated efficacy against HER2-expressing xenografts in mice. Structural studies suggest that Affibody molecules and
trastuzumab bind to different
epitopes on HER2. The aim of this study was to test the hypothesis that a combination of PNA-mediated pretargeted
radionuclide therapy and
trastuzumab treatment of HER2-expressing xenografts can extend survival compared with monotherapies. Methods: Mutual interference of the primary pretargeting probe
ZHER2:342-SR-HP1 and
trastuzumab in binding to HER2-expressing cell lines was investigated in vitro.
Experimental therapy evaluated the survival of mice bearing HER2-expressing SKOV-3 xenografts
after treatment with vehicle,
trastuzumab only, pretargeting using Affibody-PNA chimera
ZHER2:342-SR-HP1 and complementary probe 177Lu-HP2, and combination of
trastuzumab and pretargeting. The ethical permit limited the study to 90 d. The animals' weights were monitored during the study. After study termination, samples of liver and kidneys were evaluated by a veterinary pathologist for toxicity signs. Results: The presence of a large molar excess of
trastuzumab had no influence on the affinity of
ZHER2:342-SR-HP1 binding to HER2-expressing cells in vitro. The affinity of
trastuzumab was not affected by a large excess of
ZHER2:342-SR-HP1 The median survival of mice treated with
trastuzumab (75.5 d) was significantly longer than the survival of mice treated with a vehicle (59.5 d). Median survival of mice treated with pretargeting was not reached by day 90. Six mice of 10 in this group survived, and 2 had complete remission. All mice in the combination treatment group survived, and
tumors in 7 mice had disappeared at study termination. There was no significant difference between animal weights in the different treatment groups. No significant pathologic alterations were detected in livers and kidneys of treated animals. Conclusion: Treatment of mice bearing HER2-expressing xenografts with the combination of
trastuzumab and Affibody-mediated PNA-based
radionuclide pretargeting significantly increased survival compared with monotherapies. Cotreatment was not toxic for normal tissues.