HER2-targeted Theranostic Radioimmunoconjugates for SPECT Imaging and α-particle Radioimmunotherapy of HER2-positive Breast Cancer
Year: 2025
Type: dissertation
Abstract: The human epidermal growth factor receptor 2 (HER2) is overexpressed in 15–20% of breast cancer (BC) patients. HER2-targeting antibody trastuzumab IgG and its smaller molecular weight fragments trastuzumab F(ab′)2 and Fab were modified with the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA) and radiolabeled with γ-emitting 111In for SPECT imaging and α-emitting 225Ac for radioimmunotherapy (RIT) as theranostic 225Ac/111In pairs. [111In]In-DOTA-trastuzumab IgG exhibited saturable and specific binding to HER2-overexpressing BC cells in vitro (KD = 1.2 ± 0.3 × 10–8 mol/L). [225Ac]Ac-DOTA-trastuzumab IgG significantly reduced clonogenic survival and induced DNA DSBs in HER2-overexpressing BC cells in vitro. SPECT/CT and biodistribution at 48 h p.i. revealed high and HER2-specific tumour uptake of [111In]In-DOTA-trastuzumab IgG in NRG mice with HER2-overexpressing human BC xenografts. [111In]In-DOTA-trastuzumab F(ab′)2 and Fab demonstrated saturable and specific binding to HER2-overexpressing BC cells in vitro (KD = 1.2 ± 0.3 × 10–7 and 1.4 ± 0.3 × 10–7 mol/L, respectively). Tumours of NRG mice with HER2-overexpressing human BC xenografts were well-visualized on SPECT/CT images at 2 d p.i. with [111In]In-DOTA-trastuzumab IgG and F(ab′)2, but not at 18 h p.i. using [111In]In-DOTA-trastuzumab Fab. Radiation absorbed doses in the tumour was highest for [225Ac]Ac-DOTA-trastuzumab F(ab′)2 (2.88 ± 0.12 Gy), while [225Ac]Ac-DOTA-trastuzumab IgG and Fab deposited 0.84–1.32 Gy when estimated at a therapeutic total dose of 6 kBq. [225Ac]Ac-DOTA-trastuzumab IgG and Fab were characterized by a high spleen dose (17.4 ± 2.4 Gy) and high kidney dose (7.92 ± 0.48 Gy), respectively. Administration of 2 and 4 kBq of [225Ac]Ac-DOTA-trastuzumab IgG, F(ab′)2, and Fab separated by 8 d in mice with HER2-overexpressing human BC xenografts equivalently inhibited tumour growth, but [225Ac]Ac-DOTA-trastuzumab F(ab′)2 demonstrated the strongest survival advantage. In healthy NRG mice, [225Ac]Ac-DOTA-trastuzumab IgG induced acute hematopoietic toxicity, but not [225Ac]Ac-DOTA-trastuzumab F(ab′)2 and Fab. CED of 1.5 kBq of [225Ac]Ac-DOTA-trastuzumab F(ab′)2 in the tumours of mice with HER2-overexpressing human BC xenografts in the brain deposited high doses of 11.1 Gy, with low activities observed in normal tissues. CED of [225Ac]Ac-DOTA-trastuzumab F(ab′)2 induced significant tumour growth inhibition and prolonged survival. These results suggest that theranostic HER2-targeting radioimmunoconjugates for SPECT imaging and α-particle RIT are promising for detection and treatment of HER-positive BC.
Source: TSpace (University of Toronto)
Author: Kondo, Misaki
Institution: University of Toronto
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7132989923