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

2024; Society of Nuclear Medicine and Molecular Imaging; Volume: 65; Issue: 5 Linguagem: Inglês

10.2967/jnumed.123.266309

1535-5667

Frédéric Massière, Norbert Wiedemann, Inês Borrego, Aileen Hoehne, Frank Osterkamp, Matthias Paschke, Dirk Zboralski, Anne Schümann, Anne Bredenbeck, Franck Brichory, Antoine Attinger,

Coagulation, Bradykinin, Polyphosphates, and Angioedema

The membrane protein carbonic anhydrase IX (CAIX) is highly expressed in many hypoxic or von Hippel-Lindau tumor suppressor–mutated tumor types. Its restricted expression in healthy tissues makes CAIX an attractive diagnostic and therapeutic target. DPI-4452 is a CAIX-targeting cyclic peptide with a DOTA cage, allowing radionuclide chelation for theranostic purposes. Here, we report CAIX expression in multiple tumor types and provide in vitro and in vivo evaluations of 68 Ga-labeled DPI-4452 ([ 68 Ga]Ga-DPI-4452) and 177 Lu-labeled DPI-4452 ([ 177 Lu]Lu-DPI-4452). Methods: CAIX expression was assessed by immunohistochemistry with a panel of tumor and healthy tissues. The molecular interactions of complexed and uncomplexed DPI-4452 with CAIX were assessed by surface plasmon resonance and cell-binding assays. In vivo characterization of radiolabeled and nonradiolabeled DPI-4452 was performed in HT-29 colorectal cancer (CRC) and SK-RC-52 clear cell renal cell carcinoma (ccRCC) human xenograft mouse models and in healthy beagle dogs. Results: Overexpression of CAIX was shown in several tumor types, including ccRCC, CRC, and pancreatic ductal adenocarcinoma. DPI-4452 specifically and selectively bound CAIX with subnanomolar affinity. In cell-binding assays, DPI-4452 displayed comparably high affinities for human and canine CAIX but a much lower affinity for murine CAIX, demonstrating that the dog is a relevant species for biodistribution studies. DPI-4452 was rapidly eliminated from the systemic circulation of beagle dogs. The highest uptake of [ 68 Ga]Ga-DPI-4452 and [ 177 Lu]Lu-DPI-4452 was observed in the small intestine and stomach, 2 organs known to express CAIX. Uptake in other organs (e.g., kidneys) was remarkably low. In HT-29 and SK-RC-52 xenograft mouse models, both [ 68 Ga]Ga-DPI-4452 and [ 177 Lu]Lu-DPI-4452 showed tumor-selective uptake; in addition, [ 177 Lu]Lu-DPI-4452 significantly reduced tumor growth. These results demonstrated the theranostic potential of DPI-4452. Conclusion: DPI-4452 selectively targets CAIX. [ 68 Ga]Ga-DPI-4452 and [ 177 Lu]Lu-DPI-4452 localized to tumors and were well tolerated in mice. [ 177 Lu]Lu-DPI-4452 demonstrated strong tumor growth inhibition in 2 xenograft mouse models. Thus, the 2 agents potentially provide a theranostic approach for selecting and treating patients with CAIX-expressing tumors such as ccRCC, CRC, and pancreatic ductal adenocarcinoma.