A dual-labeled anti-FAP antibody for imaging and targeted photodynamic therapy of cancer associated fibroblasts in a pancreatic cancer mouse model

Ziel/Aim:

Pancreatic ductal adenocarcinoma (PDAC) is dominated by an intense desmoplastic reaction with abundant extra-cellular matrix[1]. This impacts the metabolic and immune tumor microenvironment. Activated cancer associated fibroblasts (CAFs), expressing fibroblast activation protein (FAP), play a role in this desmoplastic reaction [2]. Specific elimination of CAFs in PDAC potentially restores the aberrant tumor microenvironment. Therefore we developed a dual-labeled anti-FAP monoclonal antibody for SPECT imaging and targeted photodynamic therapy (PDT) of CAFs in PDAC.

Methodik/Methods:

The anti-FAP monoclonal humanized IgG1 antibody 28H1 was conjugated with either DTPA for imaging studies or with DTPA and the photosensitizer IRDye700DX for therapy studies. Ptf1a^wt/Cre;Kras^wt/LSL-G12D;p53^fl/fl mice, developing spontaneous PDAC, where injected with 10MBq [¹¹¹In]-In-DTPA-28H1 or dual-labeled [¹¹¹In]-In-DTPA-28H1-IRDye700DX (50ug/mouse) and SPECT/CT imaging and biodistribution studies were performed 24h post injection. One mouse was subjected to PDT by exposing the tumor to 50J/cm² 690nm light 24h post injection. One hour after illumination, tumor tissue was collected and cell death was analyzed by immunohistochemistry.

Ergebnisse/Results:

Both [¹¹¹In]-In-DTPA-28H1 (n = 1) and dual-labeled [¹¹¹In]-In-DTPA-28H1-IRDye700DX (n = 4) are efficiently taken up in the tumor (24.32%ID/g vs. 13.12 ± 3.55%ID/g), and show low residual blood activity (12.09%ID/g vs. 8.22 ± 4.17%ID/g) after 24 hours. Conjugation of IRDye700DX induces increased accumulation in the liver (4.6%ID/g vs. 15.86 ± 4.23%ID/g), but does not compromise tumor-targeting. Ex vivo immunohistochemistry showed that upon exposure, expression of apoptosis marker cleaved caspase-3 increased in the tumor tissue compared to non-irradiated internal and external control.

Schlussfolgerungen/Conclusions:

The dual-labeled anti-FAP antibody targets PDAC in mice with good signal-to-background ratios and favorable biodistribution. Furthermore, it efficiently induces cell death upon PDT, indicating that FAP-targeted PDT is a feasible and promising approach to deplete CAFs in PDAC.

Literatur/References:

[1] von Ahrens, D., et al., The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol, 2017. 10(1): p. 76.

[2] Neesse, A., et al., Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut, 2015. 64(9): p. 1476 – 84.