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

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A Correction to this article was published on 25 November 2022

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Abstract

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 (KD) 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 89Zr-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 89Zr immuno-PET reagents.

Conclusion

89Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy.

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Acknowledgements

The authors would like to thank present and former Genentech colleagues Alexander Vanderbilt, Mark Dennis, Yvonne Chen, Diego Ellerman, Phil Hass, Jeremy Good, Maciej Paluch, Pat Mckay, Matthew Albert, Jane Grogan, Rodney Prell, and Jennifer O’Mahoney for their contributions to these studies of ZED8.

X-ray diffraction data were collected at SSRL beamline 12–2. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (P30GM133894). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. The coordinates and amplitudes for the RED8 Fab:CD8ɑ complex structure have been deposited into the Protein Databank with accession code: 7UVF.

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Authors and Affiliations

  1. Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Annie Ogasawara, Herman Gill, Shravan Sriraman, Jeff Tinianow, Stijn Jan Hein Waaijer, Jan Marik & Simon-Peter Williams

  2. Department of Structural Biology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    James R. Kiefer & Christine Yu

  3. Department of Cancer Immunology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Eugene Chiang

  4. Preclinical and Translational Pharmacokinetics, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Gregory Z. Ferl & C. Andrew Boswell

  5. Research Pathology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    James Ziai

  6. Oncology Exploratory Clinical Development, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Sandra Sanabria Bohorquez & Alex De Crespigny

  7. BioAnalytical Sciences, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Sebastian Guelman, Xiangdan Wang, Jihong Yang, Minh Michael Phan, Van Nguyen & Shan Chung

  8. Safety Assessment Pathology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Tanja Zabka

  9. Safety Assessment Toxicology, Genentech, Inc, 1 DNA Way, South San Francisco, CA, 94080, USA

    Karin Staflin

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All authors contributed to the design, execution, or analysis of one or more parts of the study, or critically reviewed manuscript drafts, and all reviewed the final manuscript.

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Correspondence to Simon-Peter Williams.

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Ogasawara, A., Kiefer, J.R., Gill, H. et al. Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy. Eur J Nucl Med Mol Imaging 50, 287–301 (2023). https://doi.org/10.1007/s00259-022-05968-6

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