PT  - JOURNAL ARTICLE
AU  - Bouleau, Alizée
AU  - Nozach, Hervé
AU  - Dubois, Steven
AU  - Kereselidze, Dimitri
AU  - Chevaleyre, Céline
AU  - Wang, Cheng-I
AU  - Evans, Michael J.
AU  - Lebon, Vincent
AU  - Maillère, Bernard
AU  - Truillet, Charles
TI  - Optimizing Immuno-PET Imaging of Tumor PD-L1 Expression: Pharmacokinetic, Biodistribution, and Dosimetric Comparisons of <sup>89</sup>Zr-Labeled Anti-PD-L1 Antibody Formats
AID  - 10.2967/jnumed.121.262967
DP  - 2022 Aug 01
TA  - Journal of Nuclear Medicine
PG  - 1259--1265
VI  - 63
IP  - 8
4099  - http://jnm.snmjournals.org/content/63/8/1259.short
4100  - http://jnm.snmjournals.org/content/63/8/1259.full
SO  - J Nucl Med2022 Aug 01; 63
AB  - PET imaging of programmed cell death ligand 1 (PD-L1) may help to noninvasively predict and monitor responses to anti–programmed cell death 1/anti-PD-L1 immunotherapies. In this study, we compared the imaging characteristics of 3 radioligands derived from the anti-PD-L1 IgG1 complement 4 (C4). In addition to the IgG C4, we produced a fragment antigen-binding (Fab) C4, as well as a double-mutant IgG C4 (H310A/H435Q) with minimal affinity for the murine neonatal Fc receptor. Methods: The pharmacokinetics, biodistribution, and dosimetry of the 3 89Zr-labeled C4 ligands were compared by longitudinal PET/CT imaging in nude mice bearing subcutaneous human non–small cell lung cancer xenografts with positive (H1975 model) or negative (A549 model) endogenous PD-L1 expression. Results: The C4 radioligands substantially accumulated in PD-L1–positive tumors but not in PD-L1–negative tumors or in blocked PD-L1–positive tumors, confirming their PD-L1–specific tumor targeting. 89Zr-Fab C4 and 89Zr-IgG C4 (H310A/H435Q) were rapidly eliminated compared with 89Zr-IgG C4. Consequently, maximal tumor-to-muscle ratios were obtained earlier, at 4 h after injection for 89Zr-Fab C4 (ratio, ∼6) and 24 h after injection for 89Zr-IgG C4 (H310A/H435Q) (ratio, ∼9), versus 48 h after injection for 89Zr-IgG C4 (ratio, ∼8). Background activity in nontumor tissues was low, except for high kidney retention of 89Zr-Fab C4 and persistent liver accumulation of 89Zr-IgG C4 (H310A/H435Q) compared with 89Zr-IgG C4. Dosimetry estimates suggested that the C4 radioligands would yield organ-absorbed doses tolerable for repeated clinical PET imaging studies. Conclusion: This study highlights the potential of designing radioligands with shorter pharmacokinetics for PD-L1 immuno-PET imaging in a preclinical model and encourages further clinical translation of such radioligands.