Abstract
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 γ- and therapeutic α- and β−-emitting radionuclides for the detection and treatment of HER2pos brain lesions in a preclinical setting. 2Rs15d was radiolabeled with 111In, 225Ac and 131I 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 131I- and 225Ac-labeled sdAbs and compared to anti-HER2 monoclonal antibody (mAb) trastuzumab in two different HER2pos tumor models. Radiolabeled 2Rs15d showed high and specific tumor uptake in both HER2pos SK-OV-3-Luc-IP1 and HER2pos MDA-MB-231Br brain lesions, whereas radiolabeled trastuzumab was unable to accumulate in intracranial SK-OV-3-Luc-IP1 tumors. Administration of [131I]-2Rs15d and [225Ac]-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 HER2pos metastatic cancer.
Highlights
To this day metastasis to the brain is still a death sentence for breast cancer patients with otherwise treatable primary tumor types
In recent years there has been a steadily increasing incidence of brain metastasis, partly due to advanced imaging modalities leading to earlier detection, as well as emerging targeted treatments resulting in prolongation of survival from the primary tumor [3,4]
In the age before trastuzumab availability, HER2pos cancers had a threefold increased probability to metastasize to the lungs, liver, and brain compared with HER2neg cancers [7]
Summary
To this day metastasis to the brain is still a death sentence for breast cancer patients with otherwise treatable primary tumor types. The combination of a well-treatable primary tumor type with a high potential for CNS metastasis, and therapeutics that are unable to adequately reach the CNS, is the reason for brain metastasis becoming one of the major clinical challenges To address this need, there has been a shift in drug development towards smaller targeting compounds with better tissue penetration and higher lethality towards cancer cells [11,12]. We describe the use of the anti-HER2 sdAb 2Rs15d, coupled to 111 In or 131 I for detection via μSPECT/CT, and coupled to 131 I or 225 Ac for targeted radionuclide therapy (TRNT) of HER2pos brain lesions and compare its therapeutic efficacy and systemic toxicity to that of trastuzumab, a clinically-approved anti-HER2 treatment. The integration of molecular imaging in case of the theranostic radionuclide 131I was included to predict therapeutic efficacy during treatment
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