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Identification and characterization of a peptide with affinity to head and neck cancer
Eva-Maria Nothelfer1, Sabine Zitzmann-Kolbe, Regine Garcia-Boy
1Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany. E.Nothelfer@dkfz.de
Unlabelled:
Combination therapy has improved the quality of life for patients with squamous cell carcinomas of the head and neck (HNSCCs) but has not decisively changed prognosis. Targeted therapies, which enhance accumulation of the drug in the tumor, may be realized using tumor-specific binding peptides. This paper identifies and characterizes an HNSCC affine peptide.
Methods:
From a phage library comprising 10(9) different displayed peptides, 1 peptide was enriched after 5 in vitro selection rounds on HNO223 tumor cells. Subsequently, the gained peptide sequence H(2)N-SPRGDLAVLGHKY-CONH(2) (HBP-1) was synthesized as an amide and labeled with (125)I. In vitro studies for binding kinetics and competition were performed with 5 different HNSCC cell lines. Furthermore, the stability of the peptide was evaluated in human serum. The in vivo biodistribution of (131)I-labeled peptide was determined in HNSCC tumor-bearing nude mice. The results were further validated in human HNSCC tumor tissue sections using fluorescence-labeled HBP-1. Competition experiments were performed to determine the binding sequence and validate the target.
Results:
The HBP-1 motif was enriched in 62% of all phages sequenced. Labeled (125)I-HBP-1 showed binding to 5 different HNSCC cell lines and a maximum binding to HNO97 cells, with 11% of the applied dose per 10(6) cells and an inhibitory concentration of 50% of 38.9 nM. Stability experiments in human serum showed a half-life of 55 min. In 2 different HNSCC tumor xenografts, (131)I-HBP-1 accumulated rapidly, with stable uptake until 45 min after intravenous application. Peptide immunohistochemistry of HNSCC tissue sections exhibited tumor staining by HBP-1, whereas normal tissue remained negative. Sequence mutation and competition experiments revealed that the intrinsic RGD motif in combination with the intrinsic LXXL motif is responsible for the binding ability of HBP1. The RGDLXXL sequence within this peptide is known and indicates that binding occurs via the alpha(v)beta(6) rather than the alpha(v)beta(3) integrin.
Conclusion:
Within the sequence of HBP-1 is a RGDLXXL motif, and most likely it is targeting the alpha(v)beta(6) receptor of the integrin family of cell adhesion receptors. HBP-1 represents a promising lead structure for the development of targeted therapies or diagnostic procedures in patients with HNSCC.
Insights
Researchers identified a novel peptide, HBP-1, that specifically binds to head and neck squamous cell carcinomas (HNSCCs). This peptide shows potential for developing targeted therapies and diagnostic tools for HNSCC patients, improving treatment outcomes.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Combination therapy for head and neck squamous cell carcinomas (HNSCCs) has improved patient quality of life but not significantly altered prognosis.
- Targeted therapies using tumor-specific binding peptides can enhance drug accumulation in tumors.
- Development of novel peptides for HNSCC is crucial for advancing treatment strategies.
Purpose of the Study:
- To identify and characterize a peptide with high affinity for HNSCC.
- To evaluate the potential of this peptide for targeted therapy and diagnostics in HNSCC.
Main Methods:
- Enrichment of a peptide from a phage display library against HNSCC cells (HNO223).
- Synthesis, labeling (with 125I and 131I), and in vitro/in vivo characterization of the peptide (HBP-1).
- Assessment of binding kinetics, stability in human serum, biodistribution in tumor-bearing mice, and validation in human HNSCC tissue sections.
Main Results:
- The peptide HBP-1 demonstrated specific binding to five HNSCC cell lines, with maximum binding to HNO97 cells.
- In vivo studies showed rapid accumulation of (131)I-HBP-1 in HNSCC xenografts, with tumor-specific staining observed in human tissue sections.
- HBP-1 contains an RGDLXXL motif, indicating binding to the alpha(v)beta(6) integrin receptor.
Conclusions:
- HBP-1 targets the alpha(v)beta(6) integrin receptor, a cell adhesion receptor in the integrin family.
- HBP-1 is a promising lead structure for developing targeted therapies and diagnostic procedures for HNSCC patients.
