6S8V

Structure of the high affinity Anticalin P3D11 in complex with the human CD98 heavy chain ectodomain

Summary for 6S8V

• Entry DOI: 10.2210/pdb6s8v/pdb
• Descriptor: Neutrophil gelatinase-associated lipocalin, 4F2 cell-surface antigen heavy chain, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: lipocalin, lcn2, anticalin, lipocalin-based binding protein, cd98hc, 4f2hc, amino acid transport, presentation of cd98 light chains, interaction with integrin beta subunits, single-pass type ii membrane protein, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 137420.47

Authors

Schiefner, A.,Deuschle, F.-C.,Skerra, A. (deposition date: 2019-07-10, release date: 2020-03-04, Last modification date: 2024-10-16)

Primary citation

Deuschle, F.C.,Morath, V.,Schiefner, A.,Brandt, C.,Ballke, S.,Reder, S.,Steiger, K.,Schwaiger, M.,Weber, W.,Skerra, A.
Development of a high affinity Anticalin®directed against human CD98hc for theranostic applications.
Theranostics, 10:2172-2187, 2020

PubMed 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. : 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 Zr and investigated by positron emission tomography (PET) of CD98-positive tumor xenograft mice. : 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. 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 Zr-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. : Our findings provide a first proof of concept to exploit CD98hc for non-invasive biomedical imaging. The novel Anticalin-based αhCD98hc radiopharmaceutical constitutes a promising tool for preclinical and, potentially, clinical applications in oncology.

PubMed: 32089738
DOI: 10.7150/thno.38968

Experimental method

X-RAY DIFFRACTION (1.8 Å)