Preclinical Evaluation of a Novel Carbonic Anhydrase IX-Targeting 68Ga/177Lu Theranostic Pair for Clear Cell Renal Cell Carcinoma

Abstract Background Carbonic anhydrase IX (CAIX) is a hypoxia-regulated enzyme overexpressed in clear cell renal cell carcinoma (ccRCC) but minimally in normal tissues, making it a promising theranostic target. Current imaging modalities for ccRCC face limitations in accuracy and nephrotoxicity, while systemic therapies are constrained by resistance and variable efficacy. This study evaluates a novel CAIX-targeting theranostic pair, ⁶⁸Ga/¹⁷⁷Lu-NYM080, for imaging and therapy in preclinical ccRCC models. Results The in vivo and ex vivo biodistribution of ⁶⁸Ga/¹⁷⁷Lu-NYM080 was evaluated in CAIX-positive OS-RC-2 xenograft bearing models, and the therapeutic efficacy of ¹⁷⁷Lu -NYM080 (74 MBq single dose vs. 74 MBq×2 doses) was also investigated. NYM080 exhibited high CAIX affinity (Kd = 9.69 ± 0.46 nM). ⁶⁸Ga-NYM080 showed rapid tumor uptake (peak 10.05%ID/g at 30 min) and specificity (blocking reduced uptake by 55%). Tumor-to-muscle ratios reached 6.5 at 1h. ¹⁷⁷Lu-NYM080 demonstrated prolonged tumor retention (8.79%ID/g at 168 h) and a trend toward enhanced therapeutic efficacy with increased dosing: single dose of 74 MBq delayed tumor doubling to 13.0 days (vs. control, P = 0.064), while 74 MBq×2 doses extended it to 19.5 days (P = 0.0054 vs. control). Minimal off-target uptake and no acute toxicity were observed. Conclusion ⁶⁸Ga/¹⁷⁷Lu-NYM080 is a promising theranostic pair for ccRCC, combining high tumor specificity, prolonged tumor retention, and favorable therapeutic efficacy.