[177Lu]XYIMSR-01, a Theranostic for Targeting Carbonic Anhydrase IX

Objectives We aim to develop a low-molecular-weight (LMW) theranostic agent for detection and treatment of cancers expressing carbonic anhydrase IX (CAIX). CAIX is over-expressed in 95% of cases of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer. Although the majority of patients with ccRCC will present with clinically localized disease, up to 30% will experience recurrence after surgery. Targeted radiopharmaceutical therapy (RPT) may complement surgery and other therapies for ccRCC, particularly those that have become inoperable or metastatic.

Methods We synthesized a dual-motif, LMW inhibitor of CAIX, [¹⁷⁷Lu]XYIMSR-01 for imaging and RPT of CAIX-expressing tumors. Binding affinity and in vitro uptake of [¹⁷⁷Lu]XYIMSR-01 were measured in CAIX-expressing SK-RC-52 cells. We determined [¹⁷⁷Lu]XYIMSR-01 biodistribution and ability to detect SK-RC-52 xenografts in mouse using single-photon emission computed tomography/computed tomography (SPECT/CT). We also evaluated the ability for [¹⁷⁷Lu]XYIMSR-01 to delay SK-RC-52 tumor growth in mice. Two dose levels were investigated, each applied once: 11.1 or 18.5 MBq (300 or 500 μCi).

Results [¹⁷⁷Lu]XYIMSR-01 was generated in radiochemical yields of 60 ± 12% (n = 12) and specific radioactivity of 70.3 ± 25.9 GBq/[[Unsupported Character - Symbol Font ]]mol (1,900 ± 700 Ci/mmol, n = 12). The IC₅₀ value for [Lu]XYIMSR-01 towards CAIX was 122.4 ± 3.8 nM. [¹⁷⁷Lu]XYIMSR-01 exhibited CAIX specific uptake in vitro. SPECT/CT imaging demonstrated tumor visualization by 1 h post-injection and achieved high signal contrast by 24 h. Biodistribution studies confirmed the SPECT/CT data. Tumor-to-blood, muscle, and kidney ratios were 607.4 ± 200.7, 128.4 ± 25.4 and 4.5 ± 1.4, respectively, at 24 h post-injection. Radiotherapeutic doses of [¹⁷⁷Lu]XYIMSR-01 delayed the growth of SK-RC-52 in xenografts compared with non-treated animals.

Conclusions [¹⁷⁷Lu]XYIMSR-01 is a promising theranostic agent targeting CAIX-expressing tumors, especially ccRCC in the context of local and metastatic disease.

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