7uvf
Crystal structure of ZED8 Fab complex with CD8 alpha
Structural highlights
DiseaseCD8A_HUMAN Defects in CD8A are a cause of familial CD8 deficiency (CD8 deficiency) [MIM:608957. Familial CD8 deficiency is a novel autosomal recessive immunologic defect characterized by absence of CD8+ cells, leading to recurrent bacterial infections. FunctionCD8A_HUMAN Identifies cytotoxic/suppressor T-cells that interact with MHC class I bearing targets. CD8 is thought to play a role in the process of T-cell mediated killing. CD8 alpha chains binds to class I MHC molecules alpha-3 domains. Publication Abstract from PubMedBACKGROUND: 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 CD8alpha at a binding site approximately 9 A 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. Preclinical development of ZED8, an (89)Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.,Ogasawara A, Kiefer JR, Gill H, Chiang E, Sriraman S, Ferl GZ, Ziai J, Bohorquez SS, Guelman S, Wang X, Yang J, Phan MM, Nguyen V, Chung S, Yu C, Tinianow J, Waaijer SJH, De Crespigny A, Marik J, Boswell CA, Zabka T, Staflin K, Williams SP Eur J Nucl Med Mol Imaging. 2023 Jan;50(2):287-301. doi: , 10.1007/s00259-022-05968-6. Epub 2022 Oct 22. PMID:36271158[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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