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.

In three-dimensional (3D) spheroids, compound 45 reduced the cumulative spheroid area approximately 10-fold more than the single-target inhibitors FK866 or SLC-0111 and induced apoptosis through NAD depletion, mitochondrial dysfunction, and suppression of ERK/mTOR signaling. These results support dual hCA IX/XII-NAMPT inhibition as an effective strategy to impair tumor growth and survival under hypoxic stress.

P1, N=24, Not yet recruiting, Institut Cancerologie de l'Ouest

[89Zr]Zr-girentuximab PET/CT is a sensitive imaging method and offers promise for novel theranostics for mTNBC patients.

A recent phase III trial (ZIRCON) is widely believed to have laid the groundwork for United States Food and Drug Administration approval of the CAIX monoclonal antibody 89Zr-girentuximab...Further, emerging new targeted radiotracers and techniques such as imaging biomarker discovery with artificial intelligence will bolster those concepts. In this manual, we synthesize key data into a recommended approach.

P1/2, N=100, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Oct 2025 --> Oct 2027

To address this issue, we report a mechano-responsive ferrocene-bearing micelle that mimics the CAIX/NFS1 axis via ultrasound-activated iron release and the co-delivery of SLC-0111, a CAIX inhibitor...The in vivo efficacy studies in a 4 T1 breast cancer model confirmed potent tumor suppression with minimal systemic toxicity. This work introduces a mechanical force-controlled strategy as a substitute for CAIX/NFS1 synthetic lethality therapy without the interference of oxygen level, holding promise for advancing tumor-specific therapy.

P3, N=40, Not yet recruiting, Telix Pharmaceuticals (Innovations) Pty Limited

Recombinant-enzyme assays validated these predictions: SB-203207, SB-203208 and sulfadixiamycin A inhibited CA IX esterase activity with IC₅₀ = 73 ± 1, 99 ± 2, and 114 ± 3 nM, respectively, versus 41 ± 1 nM for reference acetazolamide...SwissADME/ADMETlab profiling highlighted SB-203207 as the most developable hit. Together, these results establish entrance-channel plugging as an alternative mechanism for CA IX inhibition, identify SB-203207 as a potent and isoform-selective lead.

Moreover, X-ray crystallography data provided insights into the CA inhibition mechanism, suggesting that these compounds behave similarly to classical CAIs. In summary, this original TDP pharmacophore effectively inhibits human CAs, with relative selectivity towards hCA IX over cytosolic isoforms, thus providing structural insights for the development of a new class of selective anticancer agents.