Abstract
Positron emission tomography (PET) imaging of programmed cell death ligand 1 (PD-L1) may help to non-invasively predict and monitor responses to anti-PD-1/anti-PD-L1 immunotherapies. In this study, we compared the imaging characteristics of three radioligands, derived from the anti-PD-L1 IgG1 C4. In addition to the IgG C4, we produced a fragment antigen-binding (Fab) C4, and a double mutant IgG C4 (H310A/H435Q), with minimal affinity for the murine neonatal Fc receptor (FcRn). Methods: The pharmacokinetics (PK), biodistribution, and dosimetry of the three 89Zr-labeled anti-PD-L1 ligands were compared by longitudinal PET/CT imaging in immunocompromised mice bearing human NSCLC xenografts with positive (H1975 model) or negative (A549 model) endogenous PD-L1 expression. Results: The 89Zr-labeled C4 ligands substantially accumulated in PD-L1+ tumors, but not in PD-L1- tumors or in blocked PD-L1+ tumors, confirming their PD-L1-specific tumor targeting. 89Zr-Fab C4 and 89Zr-IgG C4 (H310A/H435Q) were rapidly cleared from circulation compared to 89Zr-IgG C4. Consequently, maximal tumor-to-muscle ratios (TMRs) were obtained earlier, at 4 h post-injection (p.i.) for 89Zr-Fab C4 (TMR of ~6) and 24 h p.i. for 89Zr-IgG C4 (H310A/H435Q) (TMR of ~9), versus 48 h p.i. for 89Zr-IgG C4 (TMR of ~8). Background activity in non-tumor tissues was low, except for high kidney retention of 89Zr-Fab C4, and persistent liver accumulation of 89Zr-IgG C4 (H310A/H435Q) compared to 89Zr-IgG C4. Dosimetry estimates suggested that the anti-PD-L1 radioligands would yield organ absorbed doses tolerable for repeated clinical PET imaging studies. Conclusion: This study highlights the potential of designing radioligands with shorter PK for PD-L1 immunoPET imaging in a preclinical model, and encourages further clinical translation of such radioligands.
- Animal Imaging
- Molecular Imaging
- Monoclonal Antibodies
- immunotherapy
- non-small cell lung cancer (NSCLC)
- pharmacokinetics
- positron emission tomography (PET)
- programmed cell death ligand 1 (PD-L1)
- Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging, Inc.