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Development of a high affinity Anticalin^® directed against human CD98hc for theranostic applications.

ABSTRACT: Enhanced amino acid supply and dysregulated integrin signaling constitute two hallmarks of cancer and are pivotal for metastatic transformation of cells. In line with its function at the crossroads of both processes, overexpression of CD98hc is clinically observed in various cancer malignancies, thus rendering it a promising tumor target. Methods: We describe the development of Anticalin proteins based on the lipocalin 2 (Lcn2) scaffold against the human CD98hc ectodomain (hCD98hcED) using directed evolution and protein design. X-ray structural analysis was performed to identify the epitope recognized by the lead Anticalin candidate. The Anticalin - with a tuned plasma half-life using PASylation^® technology - was labeled with ⁸⁹Zr and investigated by positron emission tomography (PET) of CD98-positive tumor xenograft mice. Results: The Anticalin P3D11 binds CD98hc with picomolar affinity and recognizes a protruding loop structure surrounded by several glycosylation sites within the solvent exposed membrane-distal part of the hCD98hcED. In vitro studies revealed specific binding activity of the Anticalin towards various CD98hc-expressing human tumor cell lines, suggesting broader applicability in cancer research. PET/CT imaging of mice bearing human prostate carcinoma xenografts using the optimized and ⁸⁹Zr-labeled Anticalin demonstrated strong and specific tracer accumulation (8.6 ± 1.1 %ID/g) as well as a favorable tumor-to-blood ratio of 11.8. Conclusion: Our findings provide a first proof of concept to exploit CD98hc for non-invasive biomedical imaging. The novel Anticalin-based ?hCD98hc radiopharmaceutical constitutes a promising tool for preclinical and, potentially, clinical applications in oncology.

SUBMITTER: Deuschle FC

PROVIDER: S-EPMC7019167 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Development of a high affinity Anticalin<sup>®</sup> directed against human CD98hc for theranostic applications.

Deuschle Friedrich-Christian FC Morath Volker V Schiefner André A Brandt Corinna C Ballke Simone S Reder Sybille S Steiger Katja K Schwaiger Markus M Weber Wolfgang W Skerra Arne A

Theranostics 20200112 5

Enhanced amino acid supply and dysregulated integrin signaling constitute two hallmarks of cancer and are pivotal for metastatic transformation of cells. In line with its function at the crossroads of both processes, overexpression of CD98hc is clinically observed in various cancer malignancies, thus rendering it a promising tumor target. <b>Methods</b>: We describe the development of Anticalin proteins based on the lipocalin 2 (Lcn2) scaffold against the human CD98hc ectodomain (hCD98hcED) usin ...[more]

PMID: 32089738

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Development of a high affinity Anticalin^® directed against human CD98hc for theranostic applications.

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Development of a high affinity Anticalin<sup>®</sup> directed against human CD98hc for theranostic applications.

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Development of a high affinity Anticalin® directed against human CD98hc for theranostic applications.

Publications

Development of a high affinity Anticalin<sup>®</sup> directed against human CD98hc for theranostic applications.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Development of a high affinity Anticalin^® directed against human CD98hc for theranostic applications.