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European Journal of Nuclear Medicine and Molecular Imaging

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22-10-2022 | Molecular Imaging | Original Article

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

Authors: Annie Ogasawara, James R. Kiefer, Herman Gill, Eugene Chiang, Shravan Sriraman, Gregory Z. Ferl, James Ziai, Sandra Sanabria Bohorquez, Sebastian Guelman, Xiangdan Wang, Jihong Yang, Minh Michael Phan, Van Nguyen, Shan Chung, Christine Yu, Jeff Tinianow, Stijn Jan Hein Waaijer, Alex De Crespigny, Jan Marik, C. Andrew Boswell, Tanja Zabka, Karin Staflin, Simon-Peter Williams

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 2/2023

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 (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 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.

Available only for authorised users

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Title: Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy
Authors: Annie Ogasawara
James R. Kiefer
Herman Gill
Eugene Chiang
Shravan Sriraman
Gregory Z. Ferl
James Ziai
Sandra Sanabria Bohorquez
Sebastian Guelman
Xiangdan Wang
Jihong Yang
Minh Michael Phan
Van Nguyen
Shan Chung
Christine Yu
Jeff Tinianow
Stijn Jan Hein Waaijer
Alex De Crespigny
Jan Marik
C. Andrew Boswell
Tanja Zabka
Karin Staflin
Simon-Peter Williams
Publication date: 22-10-2022
Publisher: Springer Berlin Heidelberg
Keyword: Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 2/2023
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05968-6

ACC 2024 Congress

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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