Past, Present, and Future: Development of Theranostic Agents Targeting Carbonic Anhydrase IX

Abstract

Theranostics is the integration of diagnostic information with pharmaceuticals to increase effectiveness and safety of cancer treatments. Nuclear medicine provides a non-invasive means to visualize drug target expression across primary and metastatic sites, and assess pharmacokinetics and efficacy of companion therapeutic agents. This is significant given the increasing recognition of the importance of clonal heterogeneity in treatment response and resistance. Carbonic anhydrase IX (CA-IX) has been advocated as an attractive diagnostic and therapeutic biomarker for targeting hypoxia in solid malignancies. CA-IX confers cancer cell survival under low oxygen tension, and is associated with increased propensity for metastasis. As such, CA-IX is overexpressed in a broad spectrum of cancers. Different classes of antigen recognition molecules targeting CA-IX including monoclonal antibodies, peptides, small molecule inhibitors, and antibody mimetics have been radiolabeled for imaging and therapeutic applications. cG250, a chimeric monoclonal antibody, has been labeled with an assortment of radionuclides (124I, 111In, 89Zr, 131I, 90Y, and 177Lu) and is the most extensively investigated CA-IX radiopharmaceutical. In recent years, there have been tremendous advancements made by the research community in developing alternatives to cG250. Although still in preclinical settings, several small molecule inhibitors and antibody mimetics hold great promise in improving the management of aggressive and resistant cancers.

Quantitative Imaging of the Hypoxia-Related Marker CAIX in Head and Neck Squamous Cell Carcinoma Xenograft Models

“…In recent years, a series of CAIX-targeted imaging agents have been tested, which were elegantly reviewed in the article of Lau and colleagues recently. 25 The excellent tumor uptake of intact radiolabeled girentuximab (chimeric G250) has not been surpassed, but due to their high tumor-to-background ratios, several other radiotracers (i.e., Tc-99-acetazolamide and Tc-99-ZCAIX:2) also show great promise (Table 2). Fair comparison of these tracers is challenging due to the differences in study design, different tumor models, mice, time points, doses, etc.…”

CAIX-targeting radiotracers for hypoxia imaging in head and neck cancer models

“…In the review of Lau et al . multiple CAIX-targeting tracers with very high tumor uptake levels and tumor-to-muscle ratios were discussed 20 . The highest ratios were found in experiments in mice with ccRCC xenografts, but these tracers were not tested in a hypoxia driven model 19,24–28 .…”

“…Successful imaging with radiolabeled girentuximab-F(ab′) 2 is possible as early as 24 hours post tracer injection 18,19 . In recent years other approaches have proven to be successful as well 20 , including application of engineered molecules, called affibody molecules. Affibody molecules are small (approximately 7 kDa) affinity proteins based on non-immunoglobulin scaffold 21 .…”

New Monoclonal Antibodies for a Selective Detection of Membrane-Associated and Soluble Forms of Carbonic Anhydrase IX in Human Cell Lines and Biological Samples

“…The expression pattern of CA XII is less appropriate in the context of immunotherapy, as this enzyme is found in various normal tissues [16]. In contrast, CA IX is present only in normal small intestine, pancreas, and gastric and biliary mucosa, while it is overexpressed in many tumors like renal, bladder, colon, breast, cervix, ovary, head and neck, or lung [17,18,19]. The significance of CA IX in malignant processes, its diverse expression in normal and cancerous tissues and external localization in cells makes CA IX an attractive tumor antigen, which diagnostic and therapeutic relevance is under investigation [4,14,20].…”