Preclinical Characterization of DPI-4452: A ⁶⁸Ga/¹⁷⁷Lu Theranostic Ligand for Carbonic Anhydrase IX

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• Carbonic anhydrase IX (CAIX) is overexpressed in various hypoxic tumors, making it a promising diagnostic and therapeutic target.
• DPI-4452 is a cyclic peptide designed to target CAIX, with a DOTA cage for radionuclide attachment for theranostic applications.

Purpose of the Study:

• To evaluate CAIX expression in diverse tumor types.
• To assess the in vitro and in vivo performance of 68Ga-labeled and 177Lu-labeled DPI-4452 for CAIX-targeting theranostics.

Main Methods:

• Immunohistochemistry was used to determine CAIX expression in tumor and healthy tissues.
• Surface plasmon resonance and cell-binding assays evaluated DPI-4452 interactions with CAIX.
• In vivo studies utilized human xenograft mouse models (HT-29 CRC, SK-RC-52 ccRCC) and beagle dogs for biodistribution and efficacy assessments.

Main Results:

• CAIX was overexpressed in clear cell renal cell carcinoma (ccRCC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma.
• DPI-4452 demonstrated specific, selective binding to CAIX with subnanomolar affinity.
• [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452 exhibited tumor-selective uptake in xenograft models, with [177Lu]Lu-DPI-4452 significantly inhibiting tumor growth.

Conclusions:

• DPI-4452 selectively targets CAIX, with radiolabeled agents ([68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452) showing promising tumor localization and tolerability.
• The study supports DPI-4452's theranostic potential for patients with CAIX-expressing tumors like ccRCC, CRC, and pancreatic cancer.