What question did this study set out to answer?

This research aims to create and evaluate peptide radioligands that effectively target CAIX in clear cell renal cell carcinoma (ccRCC) for imaging and therapy.

April 5, 2026

Abstract 7190: Novel peptide radioligands targeting CAIX for theranostic applications in clear cell renal cell carcinoma (ccRCC)

Key Points

This research aims to create and evaluate peptide radioligands that effectively target CAIX in clear cell renal cell carcinoma (ccRCC) for imaging and therapy.
Used PepLib’s peptide discovery platform for ligand identification.
Evaluated peptide 4B043's binding affinity to CAIX and cross-species effectiveness.
Assessed tumor uptake and kidney accumulation in preclinical mouse models.
Advanced peptide 68Ga-4B043 into human investigational trials to measure tumor uptake in ccRCC patients.
4B043 demonstrated a sub-nanomolar affinity for CAIX with a KD of approximately 86 pM.
In mouse models, 68Ga-4B043 showed about 55% ID/g uptake in tumors with a T/K ratio of approximately 0.5.
After optimization, 2B002 achieved a T/K ratio of approximately 2, indicating improved kidney retention.
In ccRCC patients, 68Ga-4B043 displayed high uptake in renal tumors with a T/K ratio greater than 8, indicating successful targeting.

Abstract

Abstract Carbonic anhydrase IX (CAIX) is a hypoxia-inducible transmembrane enzyme highly expressed in clear cell renal cell carcinoma (ccRCC) and several other solid tumors, making it an attractive target for radiotheranostic development.Using PepLib’s peptide discovery and optimization platform, we identified a monocyclic peptide ligand, 4B043 (19 amino acids, one disulfide bond) as a high-affinity CAIX binder. 4B043 exhibited sub-nanomolar affinity to human CAIX (KD ≈ 86 pM) and strong cross-species binding to canine, mouse, and cynomolgus monkey CAIX. In Balb/c nude mice bearing VMRC-RCW tumor models, 68Ga-4B043 showed high tumor uptake (∼55 %ID/g) with a tumor-to-kidney (T/K) ratio ≈ 0.5 at 4 h post-injection. After structural optimization, 68Ga-2B002 maintained high tumor uptake while significantly reducing kidney accumulation (T/K ≈ 2 at 4 h). Encouraged by these preclinical data, 68Ga-4B043 was advanced into a human IIT. In ccRCC patients, 68Ga-4B043 demonstrated high uptake in renal tumor lesions. Due to CAXI expression in normal gastric and small intestinal tissues, 68Ga-4B043 also showed notable uptake in these organs in patients. Notably, kidney uptake was remarkably low in patients, with a tumor-to-kidney ratio 8 at 2 h, in clear contrast to the CDX model.4B043 and its optimized derivative 2B002 represent a novel class of CAIX-targeted peptide radioligands with excellent tumor uptake, favorable biodistribution, and promising translational potential. These data support their further development as theranostic agents for imaging and targeted radioligand therapy in CAIX-expressing tumors, including ccRCC. Citation Format: Weiliang (Timo) Xu, Jin Zhang, . Novel peptide radioligands targeting CAIX for theranostic applications in clear cell renal cell carcinoma (ccRCC) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7190.

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Abstract 7190: Novel peptide radioligands targeting CAIX for theranostic applications in clear cell renal cell carcinoma (ccRCC)

Key Points

Abstract

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