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
Alizée Bouleau, Hervé Nozach, Steven G. DuBois, Dimitri Kereselidze, Céline Chevaleyre, Cheng‐I Wang, Michael J. Evans, Vincent Lebon, Bernard Maillère, Charles Truillet
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). <b>Methods:</b> The pharmacokinetics (PK), biodistribution, and dosimetry of the three <sup>89</sup>Zr-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. <b>Results:</b> The <sup>89</sup>Zr-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. <sup>89</sup>Zr-Fab C4 and <sup>89</sup>Zr-IgG C4 (H310A/H435Q) were rapidly cleared from circulation compared to <sup>89</sup>Zr-IgG C4. Consequently, maximal tumor-to-muscle ratios (TMRs) were obtained earlier, at 4 h post-injection (p.i.) for <sup>89</sup>Zr-Fab C4 (TMR of ~6) and 24 h p.i. for <sup>89</sup>Zr-IgG C4 (H310A/H435Q) (TMR of ~9), versus 48 h p.i. for <sup>89</sup>Zr-IgG C4 (TMR of ~8). Background activity in non-tumor tissues was low, except for high kidney retention of <sup>89</sup>Zr-Fab C4, and persistent liver accumulation of <sup>89</sup>Zr-IgG C4 (H310A/H435Q) compared to <sup>89</sup>Zr-IgG C4. Dosimetry estimates suggested that the anti-PD-L1 radioligands would yield organ absorbed doses tolerable for repeated clinical PET imaging studies. <b>Conclusion:</b> 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.