Structure-based redesign enables clinical translation of CAIX-targeted theranostics in clear cell renal cell carcinoma.

UNLABELLED: Carbonic anhydrase IX (CAIX) is an interesting therapeutic target in clear cell renal cell carcinoma (ccRCC), but gastrointestinal uptake impedes the clinical translation of CAIX-targeted radioligand. In this study, structure-guided optimization of a cyclic peptide scaffold was conducted to decouple tumor targeting from gastrointestinal retention. METHODS: Five novel CAIX-targeting ligands were developed at the base of a cyclic peptide and evaluated in OS-RC-2 cell, small animal positron emission tomography/computed tomography (PET/CT), biodistribution, and radiotherapy experiments. The lead candidate was tested on 21 patients with cancer in comparison to 18F-FDG. RESULTS: In preclinical experiments, ⁶⁸Ga/¹⁷⁷Lu-ZH2 exhibited sub-nanomolar CAIX affinity and a favorable pharmacokinetics, with preserved tumor uptake and markedly reduced gastrointestinal retention, compared with benchmark ⁶⁸Ga/¹⁷⁷Lu-DPI-4452. In mice, ¹⁷⁷Lu-ZH2 inhibited tumor growth and prolonged survival without evident toxicity. In a first-in-human study of 21 patients with renal masses, ⁶⁸Ga-ZH2 PET/CT was deemed safe and demonstrated a superior diagnostic performance to ¹⁸F-FDG, detecting additional primary tumors and metastases with higher contrast. CONCLUSIONS: These results establish 68Ga/177Lu-ZH2 as a CAIX-targeted imaging and potential therapeutic agent with favorable preclinical and early clinical imaging characteristics, enabling the sensitive detection of ccRCC and laying the groundwork for further therapeutic investigation.