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

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.

Brain Delivery of Single-Domain Antibodies: A Focus on VHH and VNAR

“…We now discuss the potential of VHHs as theranostic tools, a combination of both diagnostic and therapeutic purposes. Puttermans et al [ 92 ] described this option with VHH 2Rs15d targeting human epidermal growth factor receptor 2 (HER2). The overexpression of this protein is associated with several cancers such as breast cancer [ 91 ].…”

Phase I Trial of 131I-GMIB-Anti-HER2-VHH1, a New Promising Candidate for HER2-Targeted Radionuclide Therapy in Breast Cancer Patients

“…Theoretically, sdAbs can be generated against virtually any cancer-specific membrane-associated protein such as for example HER2 or CD20, and bear unusually beneficial properties for targeted radionuclide therapy (TRNT) (3)(4)(5)(6)(7)(8). The human epidermal growth factor receptor type 2 (HER2) is a typical example of a membrane receptor that may be overexpressed on the cell membrane of breast, ovarian and gastric carcinoma (9).…”

Development of Radiotracers for Breast Cancer—The Tumor Microenvironment as an Emerging Target

“…Therapy with [ 111 In]In-2Rs15d and [ 225 Ac]Ac-2Rs15d resulted in prolonged survival of animals treated with [ 111 In]In-2Rs15d or [ 225 Ac]Ac-2Rs15d alone or combined with trastuzumab when compared to monotherapy with trastuzumab or buffer control. These results demonstrate 2Rs15d as a valuable vehicle for a theranostic approach in detecting and therapy of HER2 expressing brain metastases of BCa [ 26 ].…”