Therapeutic Efficacy of ²¹³Bi-labeled sdAbs in a Preclinical Model of Ovarian Cancer

Abstract

Targeted alpha-particle therapy (TAT) might be a relevant therapeutic strategy to circumvent resistance to conventional therapies in the case of HER2-positive metastatic cancer. Single-domain antibody fragments (sdAb) are promising vehicles for TAT because of their excellent in vivo properties, high target affinity, and fast clearance kinetics. This study combines the cytotoxic α-particle emitter bismuth-213 ( 213 Bi) and HER2targeting sdAbs. The in vitro specificity, affinity, and cytotoxic potency of the radiolabeled complex were analyzed on HER2 pos cells. Its in vivo biodistribution through serial dissections and via Cherenkov and micro-single-photon emission computed tomography (CT)/CT imaging was evaluated. Finally, the therapeutic efficacy and potential associated toxicity of [ 213 Bi]Bi-DTPA-2Rs15d were evaluated in a HER2 pos tumor model that manifests peritoneal metastasis. In vitro, [ 213 Bi]Bi-DTPA-2Rs15d bound HER2 pos cells in a HER2-specific way. In mice, high tumor uptake was reached already 15 min after injection, and extremely low uptake values were observed in normal tissues. Co-infusion of gelofusine resulted in a 2-fold reduction in kidney uptake. Administration of [ 213 Bi]Bi-DTPA-2Rs15d alone and in combination with trastuzumab resulted in a significant increase in median survival. We describe for the very first time the successful labeling of an HER2-sdAb with the α-emitter 213 Bi, and after intravenous administration, revealing high in vivo stability and specific accumulation in target tissue and resulting in an increased median survival of these mice especially in combination with trastuzumab. These results indicate the potential of [ 213 Bi]Bi-DTPA-sdAb as a new radioconjugate for TAT, alone and as an add-on to trastuzumab for the treatment of HER2 pos metastatic cancer.

Bismuth-213 for Targeted Radionuclide Therapy: From Atom to Bedside

“…Importantly, the radiometal-chelator complex should have a high thermodynamic stability and kinetic inertness to avoid in vivo dissociation that typically occurs via transchelation to serum proteins and enzymes. Several papers have reported that naked 213 Bi and 213 Bi dissociated from its chelating ligands tend to accumulate in the kidney [5,57,58]. In this chapter, we will give an overview of most important bifunctional chelators currently used for Bi 3+ .…”

“…The TAT studies with 213 Bi-PSMA-617 in a patient with metastasized castration-resistant prostate cancer that was refractory to 177 Luradiotherapy illustrates the potential of the combination of 213 Bi with a vector molecule with short biological half-life [88]. Further, an in vitro and in vivo preclinical studies with a 213 Bi-labeled nanobody for TAT showed promising results (see table 3) [5]. Figure 7.…”

“…These findings suggest that 213 Bi-DTPA-sdAb could be used as a new radioconjugate for TAT, both alone and in combination with trastuzumab, to treat HER2 + metastatic cancer. Also, the rapid accumulation (15 min) of 213 Bi-labeled 2Rs15d sdAb in HER2-expressing tumors demonstrates that sdAbs are promising vector molecules in combination with the short-lived 213 Bi [5].…”

“…1). A fundamental and critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand that binds the radiometal ion in a stable coordination complex so that it can be properly directed to its molecular target in vivo [5][6][7]. The radiopharmaceutical is mostly distributed within the body by the vascular system and allows targeting of a primary tumor and all its metastases.…”

“…The α-emitting radionuclide 213 Bi (T1/2 = 45.6 min, Eα = 8.4 MeV, γ = 440 keV, α-particle range = 40-80 µm) has interesting properties and might be considered as a magic bullet for TRNT [5,9]. However, like every cancer treatment modality, 213 Bi-based TAT has advantages and disadvantages.…”