[18F]AlF-RESCA-R8B4 and [68Ga]Ga-NOTA-R8B4: A Pair of Novel CD70-Targeted ImmunoPET/CT Imaging Agents for Clinical Use

Abstract Precise diagnosis of primary and metastatic clear cell renal cell carcinoma (ccRCC) is an unmet clinical challenge. CD70 is a biomarker for ccRCC, with high, consistent expression in both primary and metastatic diseases. Devising immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers targeting CD70 will enable noninvasive, accurate diagnosis of ccRCC. By immunizing alpacas with the recombinant human CD70 protein, we obtained a single-domain antibody (sdAb), R8B4, with an affinity of 9.583 nM. First, by harnessing 18F labeling, we developed a CD70 immunoPET/CT tracer, [18F]AlF-RESCA-R8B4, and verified its diagnostic accuracy in preclinical ccRCC models. Subsequently, the more readily available [68Ga]Ga-NOTA-R8B4 was constructed using 68Ga labeling, and its targeting performance was also validated. Compared with [18F]AlF-RESCA-R8B4, [68Ga]Ga-NOTA-R8B4 showed lower renal accumulation. Following this, we conducted a preliminary investigator-initiated clinical trial that demonstrated that [18F]AlF-RESCA-R8B4 clearly visualized CD70-positive metastatic lesions in ccRCC patients. With improved pharmacokinetics and reduced kidney accumulation, [68Ga]Ga-NOTA-R8B4 immunoPET/CT shows preliminary, yet promising, value for accurately detecting primary lesions in ccRCC patients. Future studies are warranted to explore the diagnostic and predictive value of the CD70-targeted immunoPET/CT imaging approaches in ccRCC patients.