89 Zr-labeled ImmunoPET targeting the cancer stem cell antigen CD133 using fully-human antibody constructs.

Autor: Wyszatko K; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada., Janzen N; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada., Silva LR; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada., Kwon L; Spatio-Temporal Targeting and Amplification of Radiation Response Innovation Centre (STTARR), University Health Network, Toronto, ON, Canada., Komal T; Spatio-Temporal Targeting and Amplification of Radiation Response Innovation Centre (STTARR), University Health Network, Toronto, ON, Canada., Ventura M; Spatio-Temporal Targeting and Amplification of Radiation Response Innovation Centre (STTARR), University Health Network, Toronto, ON, Canada., Venugopal C; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada., Singh SK; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.; Department of Surgery, McMaster University, Hamilton, ON, Canada., Valliant JF; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada., Sadeghi S; Department of Chemistry and Chemical Biology, McMaster University, Hamilton, ON, Canada. sadegs10@mcmaster.ca.
Jazyk: angličtina
Zdroj: EJNMMI research [EJNMMI Res] 2024 Mar 18; Vol. 14 (1), pp. 29. Date of Electronic Publication: 2024 Mar 18.
DOI: 10.1186/s13550-024-01091-9
Abstrakt: Background: Cancer stem cells play an important role in driving tumor growth and treatment resistance, which makes them a promising therapeutic target to prevent cancer recurrence. Emerging cancer stem cell-targeted therapies would benefit from companion diagnostic imaging probes to aid in patient selection and monitoring response to therapy. To this end, zirconium-89-radiolabeled immunoPET probes that target the cancer stem cell-antigen CD133 were developed using fully human antibody and antibody scFv-Fc scaffolds.
Results: ImmunoPET probes [ 89 Zr]-DFO-RW03 IgG (CA = 0.7 ± 0.1), [ 89 Zr]-DFO-RW03 IgG (CA = 3.0 ± 0.3), and [ 89 Zr]-DFO-RW03 scFv - Fc (CA = 2.9 ± 0.3) were radiolabeled with zirconium-89 (radiochemical yield 42 ± 5%, 97 ± 2%, 86 ± 12%, respectively) and each was isolated in > 97% radiochemical purity with specific activities of 120 ± 30, 270 ± 90, and 200 ± 60 MBq/mg, respectively. In vitro binding assays showed a low-nanomolar binding affinity of 0.6 to 1.1 nM (95% CI) for DFO-RW03 IgG (CA = 0.7 ± 0.1), 0.3 to 1.9 nM (95% CI) for DFO-RW03 IgG (CA = 3.0 ± 0.3), and 1.5 to 3.3 nM (95% CI) for DFO-RW03 scFv - Fc (C/A = 0.3). Biodistribution studies found that [ 89 Zr]-DFO-RW03 scFv - Fc (CA = 2.9 ± 0.3) exhibited the highest tumor uptake (23 ± 4, 21 ± 2, and 23 ± 4%ID/g at 24, 48, and 72 h, respectively) and showed low uptake (< 6%ID/g) in all off-target organs at each timepoint (24, 48, and 72 h). Comparatively, [ 89 Zr]-DFO-RW03 IgG (CA = 0.7 ± 0.1) and [ 89 Zr]-DFO-RW03 IgG (CA = 3.0 ± 0.3) both reached maximum tumor uptake (16 ± 3%ID/g and 16 ± 2%ID/g, respectively) at 96 h p.i. and showed higher liver uptake (10.2 ± 3%ID/g and 15 ± 3%ID/g, respectively) at that timepoint. Region of interest analysis to assess PET images of mice administered [ 89 Zr]-DFO-RW03 scFv - Fc (CA = 2.9 ± 0.3) showed that this probe reached a maximum tumor uptake of 22 ± 1%ID/cc at 96 h, providing a tumor-to-liver ratio that exceeded 1:1 at 48 h p.i. Antibody-antigen mediated tumor uptake was demonstrated through biodistribution and PET imaging studies, where for each probe, co-injection of excess unlabeled RW03 IgG resulted in > 60% reduced tumor uptake.
Conclusions: Fully human CD133-targeted immunoPET probes [ 89 Zr]-DFO-RW03 IgG and [ 89 Zr]-DFO-RW03 scFv - Fc accumulate in CD133-expressing tumors to enable their delineation through PET imaging. Having identified [ 89 Zr]-DFO-RW03 scFv - Fc (CA = 2.9 ± 0.3) as the most attractive construct for CD133-expressing tumor delineation, the next step is to evaluate this probe using patient-derived tumor models to test its detection limit prior to clinical translation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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