Human carbonic anhydrase IX (hCA IX) is markedly overexpressed in clear cell renal cell carcinoma and plays a key role in establishing an acidic tumor microenvironment associated with intrinsic chemoresistance. The resulting compounds were evaluated against hCA I, II, IX, and XII, displaying preferential inhibition of the tumor-associated isoforms. Selected derivatives (13a and 14c) showed antiproliferative activity in 786-O and CAKI-1 cells, inducing cell-cycle arrest and reducing long-term proliferative capacity more effectively than the reference CA IX inhibitor SLC-0111.

P1, N=24, Not yet recruiting, Institut Cancerologie de l'Ouest | Trial completion date: Aug 2028 --> Jan 2030 | Initiation date: Feb 2026 --> Jan 2027 | Trial primary completion date: Aug 2027 --> Jan 2029

This has prompted an effort to inhibit specific CA isoforms, as an anticancer therapeutic strategy with small molecule inhibitors, one of which (SLC-0111) completed Phase I clinical trials...Beyond small-molecule inhibitors, antibody-based approaches have reached clinical and preclinical development as imaging agents, radioimmunotherapeutics, antibody-drug conjugates, and nanomaterial conjugates. Collectively, these strategies highlight the potential of exploiting the metabolic vulnerabilities of hypoxic tumors by co-targeting CA IX/XII with complementary redox or survival pathways, paving the way toward rational polypharmacology in precision oncology.

Other forms of kidney cancer can express the marker that the imaging agent can identify. The additional analysis showed that when positive, 98% of cases were correctly identified as any form of cancer.

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.

P3, N=40, Recruiting, Telix Pharmaceuticals (Innovations) Pty Limited | Not yet recruiting --> Recruiting | Initiation date: Nov 2025 --> Mar 2026 | Trial primary completion date: Dec 2026 --> Aug 2027

Functional imaging in RCC is shifting from anatomical assessment to molecular characterisation. These advances can better select candidates for local versus systemic treatment, individualise therapy and enable novel theranostics. Further prospective trials should validate their performance and define their place in clinical pathways.

According to referring physicians, 89Zr-girentuximab PET/CT changed clinical management in six of seven patients and improved patient care in all cases. 89Zr-girentuximab PET/CT provides a noninvasive tool for characterizing indeterminate renal masses and metastatic ccRCC and may improve clinical problem-solving in complex scenarios.

P1/2, N=38, Not yet recruiting, Ospedale San Raffaele S.r.l.

Finally, single-dose [177Lu]Lu-girentuximab treatment induced cytotoxicity in PDOs in vitro and strongly reduced tumor burden in 2 independent xenografted mouse models, with no signs of toxicity. Our results demonstrate that CA-IX is a relevant target for a theragnostic strategy in mCRC, and provide the first demonstration in clinically-relevant models of metastasis that radiolabeled girentuximab can be used as a scouting agent to stratify and monitor mCRC patients and as a therapeutic alternative for patients with CA-IX-expressing tumors.

Comparison of the two most water-soluble chelators from the set of DFO, DFO* and D8W, showed that compared to [89Zr]Zr-DFO-mAb (mAb = Girentuximab), [89Zr]Zr-D8W-mAb had improved 89Zr radiolabeling kinetics and in vitro stability. Key to its utility, bone deposition of 89Zr was lower for [89Zr]Zr-D8W-mAb than [89Zr]Zr-DFO-mAb, as assessed by PET imaging in a CAIX-expressing HT-29 tumor-bearing Balb/C nude mouse model. The performance of D8W coupled with its water solubility supports its merit in its use in 89Zr-immunoPET agents.

The iridium(iii)-girentuximab conjugate described here could be of use for emissive detection of carbonic anhydrase IX positive tumour tissue to guide surgical resection as well as carbonic anhydrase IX targeted photodynamic therapy. The approach described here could be used with other tumour targeting antibodies.