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Preclinical Targeted α- and β--Radionuclide Therapy in HER2-Positive Brain Metastasis Using Camelid Single-Domain
Janik Puttemans1, Yana Dekempeneer1, Jos L Eersels1
1In vivo Cellular and Molecular Imaging laboratory, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
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.
Insights
New radiolabeled single-domain antibody fragments (sdAbs) show promise for treating HER2-positive brain metastases. These novel therapies effectively target HER2-positive brain lesions and improve survival in preclinical models, offering a potential new option for difficult-to-treat cancers.
Area of Science:
- Oncology
- Radiochemistry
- Immunotherapy
Background:
- HER2-targeted therapies have improved breast cancer outcomes, but efficacy against brain metastases remains limited.
- Metastatic brain lesions pose a significant challenge in HER2-positive breast cancer treatment.
- Camelid single-domain antibody fragments (sdAbs) offer potential for in vivo imaging and therapy due to favorable properties.
Purpose of the Study:
- To evaluate the anti-HER2 sdAb 2Rs15d, radiolabeled with diagnostic and therapeutic radionuclides, for detecting and treating HER2-positive brain metastases in a preclinical setting.
- To assess the therapeutic efficacy and toxicity of radiolabeled 2Rs15d compared to trastuzumab in HER2-positive brain tumor models.
- To investigate the potential of radiolabeled sdAbs as a treatment for HER2-positive brain metastases.
Main Methods:
- The anti-HER2 sdAb 2Rs15d was radiolabeled with 111In, 225Ac, and 131I using bifunctional chelators.
- Radiolabeled 2Rs15d and trastuzumab were evaluated in orthotopic HER2-positive brain tumor models in athymic nude mice.
- Therapeutic efficacy, survival, and systemic toxicity were assessed for radiolabeled sdAbs.
Main Results:
- Radiolabeled 2Rs15d demonstrated high and specific uptake in HER2-positive brain lesions.
- Trastuzumab showed limited accumulation in intracranial tumors, unlike radiolabeled 2Rs15d.
- Treatment with radiolabeled 2Rs15d (131I and 225Ac) significantly increased median survival in two tumor models, including those unresponsive to trastuzumab alone.
- No significant early systemic toxicity was observed with radiolabeled sdAbs.
Conclusions:
- Radiolabeled sdAbs are promising for molecular imaging and targeted radionuclide therapy of brain metastases.
- The anti-HER2 sdAb 2Rs15d shows potential as an effective agent for treating HER2-positive brain lesions.
- Radiolabeled sdAbs represent a potential valuable add-on treatment for patients with HER2-positive metastatic cancer in the brain.
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