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Targeted photodynamic therapy selectively kills activated fibroblasts in experimental arthritis
Daphne N Dorst1,2, Mark Rijpkema1, Marti Boss1
1Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
Objective:
In RA, synovial fibroblasts become activated. These cells express fibroblast activation protein (FAP) and contribute to the pathogenesis by producing cytokines, chemokines and proteases. Selective depletion in inflamed joints could therefore constitute a viable treatment option. To this end, we developed and tested a new therapeutic strategy based on the selective destruction of FAP-positive cells by targeted photodynamic therapy (tPDT) using the anti-FAP antibody 28H1 coupled to the photosensitizer IRDye700DX.
Methods:
After conjugation of IRDye700DX to 28H1, the immunoreactive binding and specificity of the conjugate were determined. Subsequently, tPDT efficiency was established in vitro using a 3T3 cell line stably transfected with FAP. The biodistribution of [111In]In-DTPA-28H1 with and without IRDye700DX was assessed in healthy C57BL/6N mice and in C57BL/6N mice with antigen-induced arthritis. The potential of FAP-tPDT to induce targeted damage was determined ex vivo by treating knee joints from C57BL/6N mice with antigen-induced arthritis 24 h after injection of the conjugate. Finally, the effect of FAP-tPDT on arthritis development was determined in mice with collagen-induced arthritis.
Results:
28H1-700DX was able to efficiently induce FAP-specific cell death in vitro. Accumulation of the anti-FAP antibody in arthritic knee joints was not affected by conjugation with the photosensitizer. Arthritis development was moderately delayed in mice with collagen-induced arthritis after FAP-tPDT.
Conclusion:
Here we demonstrate the feasibility of tPDT to selectively target and kill FAP-positive fibroblasts in vitro and modulate arthritis in vivo using a mouse model of RA. This approach may have therapeutic potential in (refractory) arthritis.
Insights
Targeted photodynamic therapy (tPDT) using an anti-fibroblast activation protein (FAP) antibody selectively destroyed FAP-positive cells in vitro and modulated arthritis in a mouse model. This approach shows potential for treating refractory rheumatoid arthritis (RA).
Area of Science:
- Immunology
- Biomedical Engineering
- Rheumatology
Background:
- Activated synovial fibroblasts expressing fibroblast activation protein (FAP) contribute to rheumatoid arthritis (RA) pathogenesis.
- Selective depletion of these FAP-positive cells presents a potential therapeutic strategy for RA.
Purpose of the Study:
- To develop and evaluate a novel targeted photodynamic therapy (tPDT) for selective destruction of FAP-positive cells.
- To assess the efficacy of tPDT in vitro and in vivo using a mouse model of RA.
Main Methods:
- Conjugation of anti-FAP antibody 28H1 with photosensitizer IRDye700DX.
- In vitro assessment of FAP-specific cell death and conjugate specificity.
- In vivo biodistribution studies in mice with and without induced arthritis.
- Ex vivo and in vivo evaluation of tPDT efficacy in modulating arthritis development.
Main Results:
- The 28H1-IRDye700DX conjugate effectively induced FAP-specific cell death in vitro.
- Photosensitizer conjugation did not affect antibody accumulation in arthritic joints.
- tPDT moderately delayed arthritis progression in a collagen-induced arthritis mouse model.
Conclusions:
- Targeted photodynamic therapy (tPDT) can selectively eliminate FAP-positive fibroblasts in vitro.
- tPDT demonstrates feasibility for modulating arthritis in vivo, suggesting therapeutic potential for refractory RA.
