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Identification of a Novel ITGαvβ6-Binding Peptide Using Protein Separation and Phage Display
Annette Altmann1,2, Max Sauter2, Saskia Roesch3,4
1Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ) Heidelberg, Germany.
Abstract:
Purpose: Targeted therapies are regarded as promising approaches to increase 5-year survival rate of head and neck squamous cell carcinoma (HNSCC) patients.Experimental design: For the selection of carcinoma-specific peptides membrane proteome of HNO97 tumor cells fractionated by the ProteomeLab PF2D system and corresponding HNO97 cells were deployed for an alternating biopanning using a sunflower trypsin inhibitor1-based phage display (SFTI8Ph) library. Stability, binding properties and affinity of novel candidates were assessed in vitro using radio-HPLC, binding experiments and surface plasmon resonance assay (SPR), respectively. Subsequently, the affinity of the peptide was verified in situ by using peptide histochemistry, in vitro using flow cytometry, and in vivo by positron emissions tomography (PET/CT).Results: We identified a novel ITGαvβ6 binding peptide (SFITGv6) containing the amino acid sequence FRGDLMQL. SFITGv6 provides stability over a period of 24 hours and demonstrates high affinity (KD = 14.8 nmol/L) for ITGαvβ6 In HNO97 cells, a maximal uptake and internalization of up to 37.3% and 37.5%, respectively, was measured. Small-animal PET imaging and biodistribution studies of HNO97 xenografted Balb/c nu/nu mice showed tumor-specific accumulation of 68Ga- and 177Lu-labeled DOTA-SFITGv6, respectively, 30 to 60 minutes after injection. Moreover, peptide histochemistry revealed a strong and homogenous binding of biotin-labeled SFITGv6 to HNSCC tumors and breast- and lung cancer-derived brain metastases. Finally, first PET/CT scans of HNSCC and NSCLC patients displayed SFITGv6 accumulation specifically in tumors, but not in inflammatory lesions.Conclusions: Thus, SFITGv6 represents a novel powerful tracer for imaging and possibly for endoradiotherapy of ITGαvβ6-positive carcinoma. Clin Cancer Res; 23(15); 4170-80. ©2017 AACR.
Insights
Researchers identified a novel peptide, SFITGv6, that specifically binds to integrin alpha-v beta-6 (ITGαvβ6). This peptide shows promise as a tracer for imaging and potentially treating ITGαvβ6-positive carcinomas, including head and neck squamous cell carcinoma.
Area of Science:
- Oncology
- Molecular Imaging
- Peptide Therapeutics
Background:
- Head and neck squamous cell carcinoma (HNSCC) survival rates can be improved with targeted therapies.
- Integrin alpha-v beta-6 (ITGαvβ6) is a potential target in various carcinomas.
Purpose of the Study:
- To identify and characterize novel carcinoma-specific peptides for targeted therapy and imaging.
- To evaluate the potential of a new peptide, SFITGv6, as a diagnostic and therapeutic agent for ITGαvβ6-positive cancers.
Main Methods:
- Alternating biopanning using a sunflower trypsin inhibitor1-based phage display (SFTI8Ph) library against HNO97 tumor cells.
- In vitro and in vivo characterization of peptide SFITGv6, including stability, binding affinity (SPR), uptake (flow cytometry), and tumor accumulation using PET/CT imaging.
- Peptide histochemistry and PET/CT scans in patients.
Main Results:
- A novel ITGαvβ6-binding peptide, SFITGv6 (FRGDLMQL), was identified with high affinity (KD = 14.8 nmol/L) and stability.
- SFITGv6 demonstrated significant tumor-specific accumulation in mouse models and in HNSCC and NSCLC patients via PET/CT imaging.
- The peptide showed specific binding to HNSCC tumors and brain metastases, distinguishing from inflammatory lesions.
Conclusions:
- SFITGv6 is a promising novel tracer for imaging ITGαvβ6-positive carcinomas.
- The peptide holds potential for targeted endoradiotherapy applications in relevant cancer types.
