Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.
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 clin...
| Publicado en: | European Journal of Nuclear Medicine & Molecular Imaging Vol. 50; no. 2; pp. 287 - 302 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , , |
| Formato: | Journal Article |
| Publicado: |
Springer Nature
Jan2023
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=161159479&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 161159479 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 16197070 NPC jtl: European Journal of Nuclear Medicine & Molecular Imaging issn: 16197070 maglogo: N pubinfo: dt: Jan2023 vid: 50 iid: 2 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 161159479 159782340 10.1007/s00259-022-05968-6 161159479 ppf: 287 ppct: 15 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy. aug: au: Ogasawara, Annie Kiefer, James R. Gill, Herman Chiang, Eugene Sriraman, Shravan Ferl, Gregory Z. Ziai, James Bohorquez, Sandra Sanabria Guelman, Sebastian Wang, Xiangdan Yang, Jihong Phan, Minh Michael Nguyen, Van Chung, Shan Yu, Christine Tinianow, Jeff Waaijer, Stijn Jan Hein De Crespigny, Alex Marik, Jan Boswell, C. Andrew affil: Department of Biomedical Imaging, Genentech, Inc, 1 DNA Way, 94080, South San Francisco, CA, USA sug: ab: 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. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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