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

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 18 F-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 68 Ga/ 177 Lu-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.