In Vivo Evaluation and Dosimetry Estimate for a High Affinity Affibody PET Tracer Targeting PD-L1
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RESEARCH ARTICLE
In Vivo Evaluation and Dosimetry Estimate for a High Affinity Affibody PET Tracer Targeting PD-L1 Daniel J Rubins ,1 Xiangjun Meng,1 Paul McQuade,1 Michael Klimas,1 Krista Getty,2 Shu-An Lin,1 Brett M. Connolly,1 Stacey S. O’Malley,1 Hyking Haley,1 Mona Purcell,1 Liza Gantert,1 Marie Holahan,1 Joel Lindgren,3 Pär Eklund,3 Caroline Ekblad,3 Fredrik Y. Frejd,3,4 Eric D. Hostetler,1 Dinko E. González Trotter,1 Jeffrey L. Evelhoch1 1
Translational Biomarkers Department, Merck & Co., Inc., West Point, PA, USA Screening and Protein Sciences Department, Merck & Co., Inc., West Point, PA, USA 3 Affibody AB, Solna, Sweden 4 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden 2
Abstract Purpose: In vivo imaging of programmed death ligand 1 (PD-L1) during immunotherapy could potentially monitor changing PD-L1 expression and PD-L1 expression heterogeneity within and across tumors. Some protein constructs can be used for same-day positron emission tomography (PET) imaging. Previously, we evaluated the PD-L1-targeting Affibody molecule [18F]AlF-NOTA-ZPD-L1_1 as a PET tracer in a mouse tumor model of human PD-L1 expression. In this study, we evaluated the affinity-matured Affibody molecule ZPD-L1_4, to determine if improved affinity for PD-L1 resulted in increased in vivo targeting of PD-L1. Procedures: ZPD-L1_4 was conjugated with NOTA and radiolabeled with either [18F]AlF or 68Ga. [18F]AlF-NOTA-ZPD-L1_4 and [68Ga]NOTA-ZPD-L1_4 were evaluated in immunocompromised mice with LOX (PD-L1+) and SUDHL6 (PD-L1-) tumors with PET and ex vivo biodistribution measurements. In addition, whole-body PET studies were performed in rhesus monkeys to predict human biodistribution in a model with tracer binding to endogenous PD-L1, and to calculate absorbed radiation doses. Results: Ex vivo biodistribution measurements showed that both tracers had 9 25 fold higher accumulation in LOX tumors than SUDHL6 ([18F]AlF-NOTA-ZPD-L1_4: LOX: 8.7 ± 0.7 %ID/g (N = 4) SUDHL6: 0.2 ± 0.01 %ID/g (N = 6), [68Ga]NOTA-ZPD-L1_4: LOX: 15.8 ± 1.0 %ID/g (N = 6) SUDHL6: 0.6 ± 0.1 %ID/g (N = 6)), considerably higher than ZPD-L1_1. In rhesus monkeys, both PET tracers showed fast clearance through kidneys and low background signal in the liver ([18F]AlF-NOTA-ZPD-L1_4: 1.26 ± 0.13 SUV, [68Ga]NOTA-ZPD-L1_4: 1.11 ± 0.06 SUV). PD-L1expressing lymph nodes were visible in PET images, indicating in vivo PD-L1 targeting. Dosimetry estimates suggest that both PET tracers can be used for repeated clinical studies, although high kidney accumulation may limit allowable radioactive doses.
Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01544-2) contains supplementary material, which is available to authorized users. Correspondence to: Daniel Rubins; e-mail: [email protected]
D.J. Rubins et al.: Evaluation of Affibody PD-L1 PET Tracer
Conclusions: [18F]AlF-NOTA-ZPD-L1_4 and [68Ga]NOTA-ZPD-L1_4 are promising candidates for same-day clinical PD-L1 PET imaging, warrantin
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