European journal of nuclear medicine and molecular imaging · 2026
A FABulous approach to image human macrophages.
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Roohani Borna, Vaughn Embs Ayla, Kumar Robin, Lee Supum, Katz Samantha R, La Prairie Chloe, Nash Dajah, Dangarwala Mann, Kluger Harriet M, Klein Daryl E, Zhang Ping, Larimer Benjamin M, Nelson Bryce, Marquez-Nostra Bernadette
Аннотация
RATIONALE: Imaging tumor-associated macrophages (TAMs) may reflect prognosis, therapeutic response and radiotheranostic potential. We report the discovery and development of a synthetic human Fab as the first immunoPET tracer targeting human CD68 (huCD68), the gold standard histopathological biomarker of pan-macrophages.
METHODS: Phage display was used to identify novel huCD68-specific Fabs. The lead Fab for immunoPET development was chosen based on expression yield and stability. Fab was conjugated to p-SCN-Bn-DFO and radiolabeled with 89Zr, yielding [89Zr]Zr-DFO-Fab. Stability and specific binding of the tracer to THP-1 macrophages were assessed in vitro. The specificity of the tracer in vivo was characterized by PET imaging of two different animal models: 1) BALB/c mice bearing huCD68 antigen- or irrelevant protein-plugs, and 2) tumor xenografted NSG mice intratumorally injected with either THP-1 macrophages or THP-1 undifferentiated cells. Finally, tumors were subjected to immunofluorescence (IF) staining of huCD68 and correlated with PET standardized uptake values (SUV).
RESULTS: Four novel huCD68-specific Fabs were identified. Fab8 was chosen as the lead based on high expression yield, purity, and stability. In vivo, [89Zr]Zr-DFO-Fab8 uptake was significantly higher in huCD68 antigen-plugs than in irrelevant protein-plugs at 1- and 4-h post-injection (p.i.). Tracer uptake in THP-1 macrophage tumors was also significantly higher than in THP-1 undifferentiated tumors at 1- and 6-h p.i.. IF of tumors confirmed higher density of huCD68 in those implanted with THP-1 macrophages than those with THP-1 undifferentiated cells. CD68 expression highly correlated with immunoPET SUV.
CONCLUSION: [89Zr]Zr-DFO-Fab8 binds specifically to huCD68, supporting the feasibility of direct PET-to-histopathogical correlation of total TAM burden.
METHODS: Phage display was used to identify novel huCD68-specific Fabs. The lead Fab for immunoPET development was chosen based on expression yield and stability. Fab was conjugated to p-SCN-Bn-DFO and radiolabeled with 89Zr, yielding [89Zr]Zr-DFO-Fab. Stability and specific binding of the tracer to THP-1 macrophages were assessed in vitro. The specificity of the tracer in vivo was characterized by PET imaging of two different animal models: 1) BALB/c mice bearing huCD68 antigen- or irrelevant protein-plugs, and 2) tumor xenografted NSG mice intratumorally injected with either THP-1 macrophages or THP-1 undifferentiated cells. Finally, tumors were subjected to immunofluorescence (IF) staining of huCD68 and correlated with PET standardized uptake values (SUV).
RESULTS: Four novel huCD68-specific Fabs were identified. Fab8 was chosen as the lead based on high expression yield, purity, and stability. In vivo, [89Zr]Zr-DFO-Fab8 uptake was significantly higher in huCD68 antigen-plugs than in irrelevant protein-plugs at 1- and 4-h post-injection (p.i.). Tracer uptake in THP-1 macrophage tumors was also significantly higher than in THP-1 undifferentiated tumors at 1- and 6-h p.i.. IF of tumors confirmed higher density of huCD68 in those implanted with THP-1 macrophages than those with THP-1 undifferentiated cells. CD68 expression highly correlated with immunoPET SUV.
CONCLUSION: [89Zr]Zr-DFO-Fab8 binds specifically to huCD68, supporting the feasibility of direct PET-to-histopathogical correlation of total TAM burden.