ImmunoPET/CT imaging of clear cell renal cell carcinoma with [¹⁸F]RCCB6: a first-in-human study

Purpose The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients. Methods Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with F-18 by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient-derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [F-18]RCCB6). Results We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [F-18]RCCB3 and [F-18]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [F-18]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [F-18]RCCB6. In a pilot translational study, [F-18]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than F-18-FDG PET/CT in a patient with ccRCC. Conclusion The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [F-18]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [F-18]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients.