Targeting the urokinase plasminogen activator receptor in triple-negative breast cancer using human antibodies for imaging and therapy

Objectives The urokinase plasminogen activator receptor (uPAR) is a promising target for the non-invasive imaging and treatment of triple-negative breast cancer (TNBC), an extremely aggressive subtype that predominantly affects young premenopausal women. Detailed here is the development of novel uPAR-targeted human antibody probes that can be radiolabeled for imaging and radioimmunotherapy (RIT).

Methods Human antibodies specific for uPAR were discovered using a human Fab phage display library. The IgG antibodies were labeled with near-IR fluorophores for optical imaging and with ¹¹¹In for SPECT imaging in MDA-MB-231 orthotopic xenografts. Mice given an intracardiac injection of MDA-MB-231 cells (dissemination model) were used to evaluate the sensitivity of ¹¹¹In-IgG and ^99mTc-Fab probes for micrometastasis detection compared to ¹⁸F- FDG-PET. An RIT study using ¹⁷⁷Lu-IgG was performed in MDA-MB-231 orthotopic xenografts. The 150 µCi dose was fractionated two weeks apart over the course of a five week study.

Results In MDA-MB-231 xenografts, fluorophore and ¹¹¹In-IgG antibodies demonstrated specific probe localization to the tumors using optical and SPECT imaging. ¹¹¹In-IgG and ^99mTc-Fab successfully imaged the tumors in the dissemination model and were found to be superior to ¹⁸F- FDG at detecting both osseous and soft-tissue metastases. At day 35 of the RIT study, animals treated with the ¹⁷⁷Lu-IgG had tumors volumes of 50 ± 43 mm³, while the saline control had volumes of 1166 ± 201 mm³.

Conclusions Human antibodies that target uPAR in TNBC preclinical models have been prepared and selected. The SPECT probes were found to be more accurate and sensitive than ¹⁸F- FDG at detecting metastatic lesions in mice. When radiolabeled with ¹⁷⁷Lu, the probes were effective RIT agents. These agents may be useful for evaluating and treating TNBC