Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy

Abstract

Objective Activated synovial fibroblasts are key effector cells in rheumatoid arthritis (RA). Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using [68Ga]Ga-FAPI-04 in an RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. Methods Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flowcytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received [68Ga]Ga-FAPI-04 and was scanned using PET/CT imaging. Results In the RA patient,FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. Conclusion In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.

Emerging Role of FAPI PET Imaging for the Assessment of Benign Bone and Joint Diseases

“…Some articles focused particularly on the role of FAPI imaging for the assessment of RA in preclinical setting, with the demonstration of the high specificity of this tracer for arthritic joints, both in vitro and in vivo. In this setting, some pilot clinical evaluations for the use of radiolabeled FAPI PET/CT in subjects with RA have also been proposed, suggesting its potential application to visualize arthritic synovium related to the specific upregulation of the expression of FAP in this site [ 10 , 30 , 31 ].…”

Highlights of Strategies Targeting Fibroblasts for Novel Therapies for Rheumatoid Arthritis

“…Unfortunately, phase I/II clinical trials with an anti-FAP monoclonal antibody in cancer treatment did not show meaningful clinical efficacy probably due to the fact that the non-toxic unconjugated monoclonal antibody did not induce cell death ( 48 ). Recently, Dorst et al ( 49 ) conjugated a near infrared dye, IRDye700DX to a monoclonal antibody (28H1) to FAP and demonstrated that in vitro 28H1-700DX was capable of killing FAP expressed fibroblast cell line (3T3) and primary synovial fibroblasts from synovial biopsy of RA patients ( 50 ). Furthermore, 28H1-700DX had moderate effect on development of CIA presumably by inducing death of FAP expressing synovial fibroblasts ( 49 ).…”

Novel PET Imaging of Inflammatory Targets and Cells for the Diagnosis and Monitoring of Giant Cell Arteritis and Polymyalgia Rheumatica

“…No reports have shown the utility of FAP targeted imaging in PMR patients to date. Yet, successful FAP targeted imaging has been demonstrated in RA patients which may point to its potential to image inflammation in PMR patients as well ( 369 ).…”