Immuno-PET Monitoring of Lymphocytes Using the CD8-Specific Antibody REGN5054.
Journal
Cancer immunology research
ISSN: 2326-6074
Titre abrégé: Cancer Immunol Res
Pays: United States
ID NLM: 101614637
Informations de publication
Date de publication:
04 10 2022
04 10 2022
Historique:
received:
25
05
2021
revised:
11
10
2021
accepted:
26
07
2022
pubmed:
28
7
2022
medline:
6
10
2022
entrez:
27
7
2022
Statut:
ppublish
Résumé
Assessment of immune-cell subsets within the tumor immune microenvironment is a powerful approach to better understand cancer immunotherapy responses. However, the use of biopsies to assess the tumor immune microenvironment poses challenges, including the potential for sampling error, restricted sampling over time, and inaccessibility of some tissues/organs, as well as the fact that single biopsy analyses do not reflect discordance across multiple intrapatient tumor lesions. Immuno-positron emission tomography (PET) presents a promising translational imaging approach to address the limitations and assess changes in the tumor microenvironment. We have developed 89Zr-DFO-REGN5054, a fully human CD8A-specific antibody conjugate, to assess CD8+ tumor-infiltrating lymphocytes (TIL) pre- and posttherapy. We used multiple assays, including in vitro T-cell activation, proliferation, and cytokine production, and in vivo viral clearance and CD8 receptor occupancy, to demonstrate that REGN5054 has minimal impact on T-cell activity. Preclinical immuno-PET studies demonstrated that 89Zr-DFO-REGN5054 specifically detected CD8+ T cells in lymphoid tissues of CD8-genetically humanized immunocompetent mice (VelociT mice) and discerned therapy-induced changes in CD8+ TILs in two models of response to a CD20xCD3 T-cell activating bispecific antibody (REGN1979, odronextamab). Toxicology studies in cynomolgus monkeys showed no overt toxicity, and immuno-PET imaging in cynomolgus monkeys demonstrated dose-dependent clearance and specific targeting to lymphoid tissues. This work supports the clinical investigation of 89Zr-DFO-REGN5054 to monitor T-cell responses in patients undergoing cancer immunotherapy.
Identifiants
pubmed: 35895745
pii: 707289
doi: 10.1158/2326-6066.CIR-21-0405
pmc: PMC9541172
mid: NIHMS1828079
doi:
Substances chimiques
Antibodies, Bispecific
0
Cytokines
0
Radioisotopes
0
Zirconium
C6V6S92N3C
Zirconium-89
NTM296JU95
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1190-1209Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001873
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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