Preclinical development of ZED8, an 89 Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.

Autor: Ogasawara A; Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Kiefer JR; Department of Structural Biology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Gill H; Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Chiang E; Department of Cancer Immunology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Sriraman S; Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Ferl GZ; Preclinical and Translational Pharmacokinetics, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Ziai J; Research Pathology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Bohorquez SS; Oncology Exploratory Clinical Development, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Guelman S; BioAnalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Wang X; BioAnalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Yang J; BioAnalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Phan MM; BioAnalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Nguyen V; BioAnalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Chung S; BioAnalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Yu C; Department of Structural Biology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Tinianow J; Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Waaijer SJH; Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., De Crespigny A; Oncology Exploratory Clinical Development, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Marik J; Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Boswell CA; Preclinical and Translational Pharmacokinetics, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Zabka T; Safety Assessment Pathology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Staflin K; Safety Assessment Toxicology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA., Williams SP; Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA. williams.simon@gene.com.
Jazyk: angličtina
Zdroj: European journal of nuclear medicine and molecular imaging [Eur J Nucl Med Mol Imaging] 2023 Jan; Vol. 50 (2), pp. 287-301. Date of Electronic Publication: 2022 Oct 22.
DOI: 10.1007/s00259-022-05968-6
Abstrakt: Background: ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1].
Methods: Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function. Immuno-PET with ZED8 was assessed in huCD8 +  tumor-bearing mice and in non-human primates. Plasma antibody levels were measured by ELISA to determine pharmacokinetic parameters, and OLINDA 1.0 was used to estimate radiation dosimetry from image-derived biodistribution data.
Results: ZED8 selectively binds to human CD8α at a binding site approximately 9 Å from that of MHCI making mutual interference unlikely. The equilibrium dissociation constant (K D ) is 5 nM. ZED8 binds to cynomolgus CD8 with reduced affinity (66 nM) but it has no measurable affinity for rat or mouse CD8. In a series of lymphoma xenografts, ZED8 imaging was able to identify different CD8 levels concordant with flow cytometry. In cynomolgus monkeys with tool compound  89 Zr-aCD8v17, lymph nodes were conspicuous by imaging 24 h post-injection, and the pharmacokinetics suggested a flat-fixed first-in-human dose of 4 mg per subject. The whole-body effective dose for an adult human was estimated to be 0.48 mSv/MBq, comparable to existing 89 Zr immuno-PET reagents.
Conclusion: 89 Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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