Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging

• DOI: 10.2967/jnumed.116.177659
• Publication Date: 2016-12-16T02:52:51Z
• Authors: Aaron T. Mayer; Arutselvan Natarajan; Sydney R. Gordon; Roy L. Maute; Melissa N. McCracken; Aaron M. Ring; Irving L. Weissman; Sanjiv S. Gambhir
• Keywords: Biodistribution; Immune checkpoint

Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still large number of patients and malignancies that do not respond to therapy. A major barrier validating biomarkers for the prediction monitoring responders clinical been lack imaging tools accurately assess dynamic immune expression. Here, we sought optimize noninvasive immuno-PET human programmed death-ligand 1 (PD-L1) expression, in preclinical model, using small high-affinity engineered protein scaffold (HAC-PD1). Six HAC-PD1 radiotracer variants were developed used biodistribution studies their ability detect PD-L1 expression vivo. Radiotracer design modifications included chelate, glycosylation, radiometal. HACA-PD1 was adopted naming convention aglycosylated tracer variants. NOD scid γ-(NSG) mice inoculated with subcutaneous tumors either be constitutively positive (CT26 hPD-L1) or negative (ΔmPD-L1 CT26) When had grown an average size cm diameter, injected 0.75-2.25 MBq (∼10 μg) variant imaged. At h after injection, organs harvested biodistribution. Of practical considered, glycosylation most prominent factor affecting uptake, specificity, clearance. In studies, 64Cu-NOTA-HACA-PD1 visualized We reasoned because scaffold's (14 kDa), its pharmacokinetics may suitable labeling short-lived widely clinically available radiometal 68Ga. 68Ga-NOTA-HACA-PD1 68Ga-DOTA-HACA-PD1 exhibited target-to-background ratios ex vivo (12.3 15.2 tumor-to-muscle ratios, respectively). Notably, all enabled much earlier detection (1 injection) than previously reported radiolabeled antibodies (>24 injection). This work provides template assessing parameters supports translation radiotracers checkpoints.