First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with (68)Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for αvβ3 Integrin Receptor Targeting

Abstract

(68)Ga-NODAGA-THERANOST™ is an αvβ3 integrin antagonist and the first radiolabeled peptidomimetic to reach clinical development for targeting integrin receptors. In this first-in-human study, the feasibility of integrin receptor peptidomimetic positron emission tomography/computed tomography (PET/CT) imaging was confirmed in patients with non-small-cell lung cancer and breast cancer.

Methods: Patients underwent PET/CT imaging with (68)Ga NODAGA-THERANOST. PET images were analyzed qualitatively and quantitatively and compared to 2-deoxy-2-((18)F) fluoro-d-glucose ((18)F-FDG) findings. Images were obtained 60 minutes postinjection of 300-500 MBq of (68)Ga-NODAGA-THERANOST.

Results: (68)Ga-NODAGA-THERANOST revealed high tumor-to-background ratios (SUVmax=4.8) and uptake at neoangiogenesis sites. Reconstructed fused images distinguished cancers with high malignancy potential and enabled enhanced bone metastasis detection. (18)F-FDG-positive lung and lymph node metastases did not show uptake, indicating the absence of neovascularization.

Conclusions: (68)Ga-NODAGA-THERANOST was found to be safe and effective, exhibiting in this study rapid blood clearance, stability, rapid renal excretion, favorable biodistribution and PK/PD, low irradiation burden (μSv/MBq/μg), and convenient radiolabeling. This radioligand might enable theranostics, that is, a combination of diagnostics followed by the appropriate therapeutics, namely antiangiogenic therapy, image-guided presurgical assessment, treatment response evaluation, prediction of pathologic response, neoadjuvant-peptidomimetic-radiochemotherapy, and personalized medicine strategies. Further clinical trials evaluating (68)Ga-NODAGA-THERANOST are warranted.

Keywords: 68Ga-NODAGA-THERANOST™; positron emission tomography; αvβ3 receptor targeting.

Figures

FIG. 1.

Structure of 68Ga-NODAGA-THERANOST.

FIG. 2.

(A) PET/CT images using 68Ga-NODAGA-THERANOST (left and right panels) as well as 18F-FDG (middle panel) of patient #1. Overall, 25 lesions were cRGD positive compared to 12 lesions detected by FDG (shown here are skeletal metastases on transverse slices in upper row: PET, middle row: CT, and lower row: fused PET/CT). Curved arrows (left panel) demonstrate cRGD positive vertebral pedicle lesions, which were negative on FDG. Straight arrows indicate FDG-avid lesion in left sacral ala (middle panel), which was cRGD negative (right panel). (B) The maximum intensity projection (A) and reconstructed fused images using 68Ga-NODAGA-THERANOST revealed intense uptake (SUVmax=4.8) at neoangiogenesis sites in multiple skeletal metastases, for example, skull (B), vertebrae (C), and pelvis (D). The 18F-FDG-positive lung (E2) and lymph node (F2) metastases did not show any uptake of 68Ga-NODAGA-THERANOST (E1 and F1, respectively), indicating the absence of neovascularization. CT, computed tomography; PET, positron emission tomography; 18F-FDG, 2-deoxy-2-(18F) fluoro-d-glucose; SUV, standardized uptake value; arrows pointing to the right indicate lung metastasis and to the left indicate lymph node metastasis.

FIG. 3.

PET/CT images using 68Ga-NODAGA-THERANOST of patient #2. (A) Demonstrates integrin receptor expression and angiogenesis in the extensive right pleural carcinomatosis. SUVmax of target lesion in the right dorsoapical pleura was 4.0 (tumor-to-liver ratio of SUVmax, T/L was 1.43 and tumor-to-spleen ratio of SUVmax, T/S was 1.48). Pleural uptake was also noted on somatostatin receptor PET/CT with 68Ga DOTATOC (B). SUVmax of the same lesion being 6.9, but with a lower target lesion-to-background ratio (T/L 0.78, T/S 0.17). MIP image on the left, coronal fused PET/CT in the middle, transverse CT on the right above, and transverse fused PT/CT on the right below. MIP images of 68Ga-NODAGA-THERANOST PET/CT are shown in two different color scales.