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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.

SUBMITTER: Lau J

PROVIDER: S-EPMC5695016 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Lau Joseph J Lin Kuo-Shyan KS Bénard François F

Theranostics 20170926 17

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 b ...[more]

PMID: 29158829

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Project description:BackgroundCarbonic anhydrase IX (CA IX) is a hypoxia-regulated transmembrane protein over-expressed in various types of human cancer. Recently, a new peptide with affinity for human carbonic anhydrase IX (CaIX-P1) was identified using the phage display technology. Aim of the present study is to characterize the binding site in the sequence of CaIX-P1, in order to optimize the binding and metabolic properties and use it for targeting purposes.Methodology/principal findingsVarious fragments of CaIX-P1 were synthesized on solid support using Fmoc chemistry. Alanine scanning was performed for identification of the amino acids crucial for target binding. Derivatives with increased binding affinity were radiolabeled and in vitro studies were carried out on the CA IX positive human renal cell carcinoma cell line SKRC 52 and the CA IX negative human pancreatic carcinoma cell line BxPC3. Metabolic stability was investigated in cell culture medium and human serum. Organ distribution and planar scintigraphy studies were performed in Balb/c nu/nu mice carrying subcutaneously transplanted SKRC 52 tumors. The results of our studies clearly identified amino acids that are important for target binding. Among various fragments and derivatives the ligand CaIX-P1-4-10 (NHVPLSPy) was found to possess increased binding potential in SKRC 52 cells, whereas no binding capacity for BxPC3 cells was observed. Binding of radiolabeled CaIX-P1-4-10 on CA IX positive cells could be inhibited by both the unlabeled and the native CaIX-P1 peptide but not by control peptides. Stability experiments indicated the degradation site in the sequence of CaIX-P1-4-10. Biodistribution studies showed a higher in vivo accumulation in the tumor than in most healthy tissues.ConclusionsOur data reveal modifications in the sequence of the CA IX affine ligand CaIX-P1 that might be favorable for improvement of target affinity and metabolic stability, which are necessary prior to the use of the ligand in clinical approaches.

Dataset Information

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

Publications

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

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