Preclinical Development and First-in-Human Imaging of the Integrin α_vβ₆ with [¹⁸F]α_vβ₆-Binding Peptide in Metastatic Carcinoma.

Abstract

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 PET. The peptide α_vβ₆-BP was prepared on solid phase and radiolabeled with 4-[¹⁸F]fluorobenzoic acid. <i>In vitro</i> testing included ELISA, serum stability, and cell binding studies using paired α_vβ₆-expressing and α_vβ₆-null cell lines. <i>In vivo</i> 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. [¹⁸F]α_vβ₆-BP displayed excellent affinity and selectivity for the integrin α_vβ₆ <i>in vitro</i> [IC₅₀(α_vβ₆) = 1.2 nmol/L <i>vs</i> IC₅₀(α_vβ₃) >10 μmol/L] 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. 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.