The folate receptor β as a macrophage-mediated imaging and therapeutic target in rheumatoid arthritis

Abstract

Macrophages play a key role in the pathophysiology of rheumatoid arthritis (RA). Notably, positive correlations have been reported between synovial macrophage infiltration and disease activity as well as therapy outcome in RA patients. Hence, macrophages can serve as an important target for both imaging disease activity and drug delivery in RA. Folate receptor β (FRβ) is a glycosylphosphatidyl (GPI)-anchored plasma membrane protein being expressed on myeloid cells and activated macrophages. FRβ harbors a nanomolar binding affinity for folic acid allowing this receptor to be exploited for RA disease imaging (e.g., folate-conjugated PET tracers) and therapeutic targeting (e.g., folate antagonists and folate-conjugated drugs). This review provides an overview of these emerging applications in RA by summarizing and discussing properties of FRβ, expression of FRβ in relation to macrophage polarization, FRβ-targeted in vivo imaging modalities, and FRβ-directed drug targeting.

Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1

“…Indeed, FOLR2 expression parallels that of CD163 in tissue-resident macrophages, TAM from various tumor types and inflamed synovium. Therefore, FRβ can be considered a macrophage-specific marker, in line with previous reports on its expression in distinct macrophage subsets in human and mouse tissues [44,45,48,72,83,84]. Further stressing its cell-restricted expression, the expression of CD163 and FOLR2 in TAM significantly correlates with the presence of the PU.1 transcription factor.…”

First in man study of [18F]fluoro-PEG-folate PET: a novel macrophage imaging technique to visualize rheumatoid arthritis

“…The use of a F-18 radio-isotope with a half-life of 110 minutes allows for central synthesis and regional distribution to other medical centers. Potential clinical applications are early diagnosis of RA and early assessment of therapeutic efficacy of FRβ-targeted macrophage therapies, which can support development of personalized medicine 29 . Moreover, fast clearance from the blood pool makes [ 18 F]fluoro-PEG-folate interesting for imaging systemic inflammation in RA and potentially other diseases (such as atherosclerosis or vasculitis), which can be depicted in one whole body imaging session.…”

“…In contrast to the α-isoform of FR [18][19][20] , FRβ is selectively expressed on both normal and malignant hematopoietic cells of the myeloid lineage, including monocytes, (tumour-associated) macrophages, and myeloid leukaemia cells [21][22][23] . Observations that FRβ expression and folate binding are induced during (synovial) macrophage activation in RA [24][25][26][27] , and exploiting the property of high binding affinity of folic acid to FRβ 25 , have encouraged the development of folate conjugates as potential macrophage imaging agents for cancer and inflammatory diseases 28,29 . Recently, [ 18 F]fluoro-PEG-folate (polyethylene glycol folate) has been proposed as a novel candidate folate-based PET tracer 30 .…”

Synovial Macrophages in Rheumatoid Arthritis: The Past, Present, and Future

“…In addition, prolactin receptor is expressed in RA and psoriatic arthritic synovial tissue and contributes to human SM (CD68 + ) activation [40]. Folate receptor beta acts as a human macrophage-(CD11b, CD14, CD16, and CD68-) mediated imaging marker and therapeutic target in RA [41]. Translocator protein acts as an imaging marker of human macrophage (CD163 and CD68) and stromal activation in RA pannus [42].…”