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

High Resolution Image Download MS PowerPoint Slide 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 18 F labeling, we developed a CD70 immunoPET/CT tracer, [ 18 F]AlF-RESCA-R8B4, and verified its diagnostic accuracy in preclinical ccRCC models. Subsequently, the more readily available [ 68 Ga]Ga-NOTA-R8B4 was constructed using 68 Ga labeling, and its targeting performance was also validated. Compared with [ 18 F]AlF-RESCA-R8B4, [ 68 Ga]Ga-NOTA-R8B4 showed lower renal accumulation. Following this, we conducted a preliminary investigator-initiated clinical trial that demonstrated that [ 18 F]AlF-RESCA-R8B4 clearly visualized CD70-positive metastatic lesions in ccRCC patients. With improved pharmacokinetics and reduced kidney accumulation, [ 68 Ga]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.