PD-L1をターゲットするPET診断及びがん免疫治療用の新規標識ペプチドの開発研究

Background:Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are recognized as promising targets for cancer immunotherapy. Binding of PD-L1 to PD-1 determines a downregulation of T-cell effector functions in cancer patients, inhibiting the antitumor immune response and leading to T-cell exhaustion. Blockade of PD-1/PD-L1 can strengthen the function of effector T cells and increase their production of cytokines through reactivation. Current medication directed toward the PD-1/PD-L1 axis includes monoclonal antibodies. Although great progress has been made, therapeutic antibodies exhibit several disadvantages such as: (1) limited tissue and tumor penetration, (2) lacking oral bioavailability, (3) immunogenicity, and (4) difficult production and high cost. Moreover, current PD-1/PD-L1 axis directed monoclonal antibodies lead to a tumor response only in a small fraction of all known tumor types. Design and Methods:The research of peptide modulator of PD-1/PD-L1 PPIs is significant for both imaging of PD-L1 of the tumor immune microenvironment and anti-cancer therapy. The main goal of this project is to develop radiolabeled PD-L1 peptide modulators with high binding affinity and high specificity. Moreover, as proof-of-concept, this project will demonstrate peptide for radiotherapy and imaging. The bacteria surface display screened a lead peptide TPP-1. Then molecular dynamics docking was performed. Based on the complex structure, the peptide was bound PD-L1 protein with β-hairpin conformation. We then labelled the peptide with 64Cu. The PET imaging of peptide in MDA-231 xenograft mice will be performed. The distribution in vivo will be quantitatively analyzed. After that, peptide cyclization strategies will be utilized to stabilize the peptide into β-hairpin conformation. Results:1. TPP-1 peptide binds to PD-L1 protein in β-hairpin Conformation.2. The C- terminal of the peptide is a well-defined β-hairpin structure, however, the N-terminal of the peptide is a random coil structure. 3. The labelled peptide is very stable in saline, and its half-life in serum is about 6 hours. 4. The labelled peptide was majorly metabolized by liver and kidney. It will be excreted by urethra.5. The labelled peptide has some specific accumulation in spleen in normal mice. Conclusion:TPP-1 peptide is a potential PET tracer for PD-L1 imaging and a lead compound for immune checkpoint therapy. Through peptide stapling technique to constrain the peptide into β-hairpin, this peptide is capable of oral administration for Immunol cancer therapy.第2回日本核医学会分科会 放射性薬品科学研究会 第18回放射性医薬品・画像診断薬研究