Preclinical development and first-in-human imaging of the integrin {alpha}v{beta}6 with [18F]{alpha}v{beta}6-Binding Peptide in metastatic carcinoma.

Purpose:The study was undertaken to develop and evaluate the potential of an integrin α_vβ₆-binding peptide (α_vβ₆-BP) for noninvasive imaging of a diverse range of malignancies with positron emission tomography (PET). Experimental Design: The peptide α_vβ₆-BP was prepared on solid phase and radiolabeled with 4-[¹⁸F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using a paired α_vβ₆-expressing and α_vβ₆-null cell lines. In vivo evaluation (PET/CT, biodistribution and autoradiography) was performed in a mouse model bearing the same paired α_vβ₆-expressing and α_vβ₆-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast or pancreatic cancer. Results: [¹⁸F]α_vβ₆-BP displayed excellent affinity and selectivity for the integrin in vitro (IC₅₀(α_vβ₆) = 1.2 nM vsIC₅₀(αβ₃) >10 μM) in addition to rapid target-specific cell binding and internalization (72.5±0.9% binding and 52.5±1.8% respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [¹⁸F]α_vβ₆-BP was rapid, primarily via the kidneys. In patients, [¹⁸F]α_vβ₆-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [¹⁸F]α_vβ₆-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver and lung. Conclusions:The clinical impact of [¹⁸F]α_vβ₆-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.

https://ift.tt/2RFvLgV