Preclinical and First-in-Human Study of Carbonic Anhydrase IX-Targeting Theranostic Pair, [68Ga]Ga/[177Lu]Lu-NYM096, in Clear Cell Renal Cell Carcinoma.

Small-molecule PET tracers targeting carbonic anhydrase IX (CAIX) have recently been developed for patients with clear cell renal cell carcinoma (ccRCC). Here, we report the preclinical results and first-in-human study of a CAIX-targeting theranostic pair, [68Ga]Ga/[177Lu]Lu-NYM096, for patients with metastatic ccRCC, aiming to assess its safety, tolerability, dosimetry, and preliminary efficacy. Methods: The in vivo biodistribution of [68Ga]Ga-NYM096 was evaluated in mice bearing OS-RC-2 xenografts. The therapeutic efficacy of [177Lu]Lu-NYM096 was assessed with a dose escalating from 8.1 to 74 MBq. Patients with metastatic ccRCC who had disease progression after standard therapy were prospectively enrolled. Serial whole-body [68Ga]Ga-NYM096 PET/CT scans were performed to evaluate biodistribution and dosimetry. Patients with positive CAIX expression entered the therapeutic phase and received [177Lu]Lu-NYM096 following a standard 3-plus-3 dose escalation design that started from 1.85 GBq. Serial whole-body planar imaging was performed after the first therapy cycle. Safety, dosimetry, and preliminary efficacy were evaluated. Results: High tumor accumulation of [68Ga]Ga/[177Lu]Lu-NYM096 was observed in OS-RC-2 xenograft tumor models. Moreover, [177Lu]Lu-NYM096 was well tolerated and demonstrated a significant dose-dependent tumor suppression effect. In the 2 patients, [68Ga]Ga-NYM096 demonstrated excellent tumor uptake, with an SUVmax of 330.0 at 1 h postinjection. Subsequent [177Lu]Lu-NYM096 treatment demonstrated no evidence of nephrotoxicity, hepatotoxicity, or pancreatic toxicity. Patient 1 experienced grade 1 gastric side effects and anemia, whereas patient 2 developed grade 3 radiation-induced gastritis. Follow-up [68Ga]Ga-NYM096 PET/CT evaluations showed evidence of tumor response to [177Lu]Lu-NYM096 treatment. Conclusion: This is early evidence that the CAIX-targeting theranostic pair [68Ga]Ga/[177Lu]Lu-NYM096 is feasible, offering a strategy for patients with end-stage ccRCC. The gastric toxicity proposes a significant challenge for CAIX-targeting radiopharmaceutical therapy.