Preclinical Targeted α- and β--Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain Antibodies

HER2-targeted therapies have drastically improved the outcome for breast cancer patients. However, when metastasis to the brain is involved, current strategies fail to hold up to the same promise. Camelid single-domain antibody-fragments (sdAbs) have been demonstrated to possess favorable properties for detecting and treating cancerous lesions in vivo using different radiolabeling methods. Here we evaluate the anti-HER2 sdAb 2Rs15d, coupled to diagnostic gamma- and therapeutic alpha- and beta(-)-emitting radionuclides for the detection and treatment of HER2(pos) brain lesions in a preclinical setting. 2Rs15d was radiolabeled with In-111, Ac-225 and I-131 using DTPA- and DOTA-based bifunctional chelators and Sn-precursor of SGMIB respectively and evaluated in orthotopic tumor-bearing athymic nude mice. Therapeutic efficacy as well as systemic toxicity were determined for I-131- and Ac-225-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2(pos) tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2(pos) SK-OV-3-Luc-IP1 and HER2(pos) MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [I-131]-2Rs15d and [Ac-225]-2Rs15d alone and in combination with trastuzumab showed a significant increase in median survival in 2 tumor models that remained largely unresponsive to trastuzumab treatment alone. Histopathological analysis revealed no significant early toxicity. Radiolabeled sdAbs prove to be promising vehicles for molecular imaging and targeted radionuclide therapy of metastatic lesions in the brain. These data demonstrate the potential of radiolabeled sdAbs as a valuable add-on treatment option for patients with difficult-to-treat HER2(pos) metastatic cancer.