First-in-human studies of [18F]αvβ6-BP, a PET imaging probe targeting the cancer-associated integrin αvβ6

50 Objectives: The integrin subtype αvβ6 is significantly upregulated in a wide range of epithelial derived cancers, plays a key role in invasion and metastasis and its expression is often associated with poor prognosis. To evaluate the potential of αvβ6-targeted imaging, we have developed the PET imaging probe [18F]αvβ6-BP, a peptide with high affinity (nM) and selectivity for the integrin αvβ6 and demonstrated favorable pharmacokinetics in tumor-bearing mice and non-human-primates (NHP). The objectives of this first-in-human study were to evaluate the safety, biodistribution and dosimetry of this αvβ6-directed imaging probe. Methods: [18F]αvβ6-BP was prepared per current good manufacturing practice (cGMP) under the guidelines of USP Chapter using N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) and the product was formulated in saline/ethanol (<10% v/v) for injection. Patients with a diagnosis of breast, colon, lung or pancreas cancer were recruited. [18F]αvβ6-BP was injected IV (<370 MBq) and patients were scanned from the apex of the skull to the proximal thighs using two minutes per bed position starting at t=30 min, 1, 2, and 3 h post injection. One regular dose CT scan was performed at 1 h and 3 low dose CTs at the other imaging time points. Blood samples (1 mL) were obtained throughout the imaging period (1, 3, 5, 10, 15, 30, 60, 90, 120, 180 min) along with vitals and EKG. When tissue biopsy samples were available immunohistochemical characterization of β6 integrin expressionwas performed. Image review was performed using GE Advantage Workstation software version 4.5. SUVmax (g/mL) values were obtained for lesions using manual sizing of rectangular ROI and 42% threshold. Results: [18F]αvβ6-BP was prepared in 15.8% (range: 13.4-19.0%) decay-corrected radiochemical yield from [18F]SFB. The imaging probe doses had molar activities >37 GBq/μmol, mass doses 99%. HPLC analysis of blood samples (30 min p.i.) indicated stability of [18F]αvβ6-BP. To date 4 breast, 3 pancreas, 2 colon and 1 lung cancer patients were enrolled in the study. In all patients [18F]αvβ6-BP was well tolerated without noticeable changes in vital signs, on EKG, or in blood laboratory results. [18F]αvβ6-BP demonstrated clearance similar to that observed in NHPs with the majority being excreted via the kidneys. Images showed uptake of [18F]αvβ6-BP in both the primary lesion and metastases, including metastasis to the liver, lung and bone, with minimal uptake observed in normal lung, liver, bone and brain. The figure shows images from a patient with metastatic pancreatic adenocarcinoma who was noted to have a stable pancreatic mass and small, indeterminate lung nodules by CT. [18F]αvβ6-BP uptake was observed in the pancreatic head/body (SUVmax=26.9, 25.2, 20.4, 17.0 at 30 min, 1, 2, 3 h respectively) and in several sub-cm lesions. Detailed image analysis is currently underway for all patients scanned to date to calculate SUVs and determine dosimetry of this novel PET imaging probe. Conclusions: [18F]αvβ6-BP can be prepared reliably for clinical imaging and is well tolerated by patients. Images obtained to date look promising with significant uptake of [18F]αvβ6-BP in both the primary lesion and in metastases in a variety of cancers, and uptake correlated with αvβ6 expression for available IHC samples. These initial results are in concurrence with the pre-clinical observations, and demonstrate the ability to successful image lesions well under 1 cm. The clinical impact of this first-in-human study is immediate for a broad spectrum of diseases. Support: DOE DESC0008385, NIH R01CA211554-01, UC Davis Research in Science and Engineering