Dual-Receptor–Targeted Radioimmunotherapy of Human Breast Cancer Xenografts in Athymic Mice Coexpressing HER2 and EGFR Using ¹⁷⁷Lu- or ¹¹¹In-Labeled Bispecific Radioimmunoconjugates

Abstract

One mechanism of resistance to trastuzumab in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) is increased epidermal growth factor receptor (EGFR) expression. We have developed 111 In-labeled bispecific radioimmunoconjugates (bsRICs) that bind HER2 and EGFR on BC cells by linking trastuzumab Fab fragments through a polyethylene glycol (PEG 24 ) spacer to epidermal growth factor (EGF). We hypothesized that tumors coexpressing HER2 and EGFR could be treated by dualreceptor-targeted radioimmunotherapy with these bsRICs labeled with the β-particle emitter 177 In-labeled trastuzumab Fab or EGF killed tumor cells that predominantly expressed HER2 or EGFR, respectively, whereas bsRICs were cytotoxic to cells that displayed either HER2 or EGFR or both receptors. bsRICs were more effective than monospecific agents. 177 Lu-DOTA-Fab-PEG 24 -EGF was more cytotoxic than 111 In-DTPAFab-PEG 24 -EGF. The tumor uptake of 177 Lu-DOTA-Fab-PEG 24 -EGF was 2-fold greater than 177 Lu-DOTA-trastuzumab Fab or 177 Lu-DOTA-EGF. The NOAEL for 177 Lu-DOTA-Fab-PEG 24 -EGF was 11.1 MBq (10 μg).Trastuzumab-sensitive MDA-MB-231/H2N and trastuzumab-resistant TrR1 tumors were growth-inhibited by 177 Lu-DOTA-Fab-PEG 24 -EGF or 111 In-DTPA-Fab-PEG 24 -EGF. Unlabeled immunoconjugates had no effect on tumor growth. 177 Lu-DOTA-Fab-PEG 24 -EGF inhibited tumor growth more effectively than 111 In-DTPA-Fab-PEG 24 -EGF because of a 9.3-fold-higher radiation-absorbed dose (55.0 vs. 5.9 Gy, respectively). Conclusion: These results are encouraging for further development of these bsRICs for dual-receptor-targeted radioimmunotherapy of BC coexpressing HER2 and EGFR, including trastuzumab-resistant tumors.

A Radiolabeled Fully Human Antibody to Human Aspartyl (Asparaginyl)β-Hydroxylase Is a Promising Agent for Imaging and Therapy of Metastatic Breast Cancer

“…22 Li et al also utilized trastuzumab, which they labeled with Auger electron emitter 111 In to kill human breast cancer cells, 23 however, their results are so far only preliminary in vitro data, and it remains to be seen if 111 In will show promise in treating experimental breast cancer in vivo. The study, where the engineered immunoconjugates labeled with more traditional radionuclide 177 Lu and targeting both HER2 and EGFR on the surface of breast cancer xenografts in mice were used, 24 demonstrated comparable efficacy and lack of toxicity observed in this work.…”

“…[22][23][24] For the pilot therapy study in 4T1 tumor-bearing mice, the authors have selected an a-emitter 213 Bi. The use of targeted therapy with aparticle emitters in oncology is burgeoning worldwide.…”

In Vivo Molecular Imaging for Biomedical Analysis and Therapies

“…The combination of 111 In (diagnosis with SPECT) or 68 Ga (half-life: 68 min, diagnosis with PET) with 177 Lu or 90 Y (therapy) is commonly used for this purpose since the same or similar chelates can be used for these radionuclides. [76][77][78][79] That is, only the radionuclides differ between diagnosis and therapy. The patient is quantitatively analyzed by SPECT or PET to investigate whether the antigens or receptors are positive or not, then the selected patient will be treated by therapeutic radionuclides.…”

Targeting the Human Epidermal Growth Factor Receptors with Immuno-PET: Imaging Biomarkers from Bench to Bedside

“…In addition, in a small-animal SPECT/CT study, a novel 111 Inlabeled bispecific agent consisting of a trastuzumab Fab fragment targeting HER2 and NRG-1 targeting HER3 has been shown to specifically accumulate in tumor xenografts in which HER2 is coexpressed with HER3 (29).…”