Efficacy of an immunotoxin to folate receptor beta in the intra-articular treatment of antigen-induced arthritis

Abstract

IntroductionWe previously demonstrated that synovial sublining macrophages express folate receptor beta (FRβ). The aim of this study was to evaluate the efficacy of intra-articular administration of a recombinant immunotoxin to FRβ for treating rat antigen-induced arthritis.MethodsA monoclonal antibody (mAb) to rat FRβ was produced by immunizing mice with B300-19 cells (murine pre-B cells) transfected with the rat FRβ gene. Recombinant immunotoxin was prepared by conjugating the Fv portion of the anti-rat FRβ mAb heavy chain with a truncated Pseudomonas exotoxin A and the Fv portion of the anti-rat FRβ mAb light chain. Antigen-induced arthritis was induced through intra-articular injection of methylated bovine serum albumin (mBSA) after two subcutaneous injections of mBSA and complete Freund's adjuvant. Immunotoxin was intra-articularly injected into the arthritis joint every other day for seven days after arthritis onset. Joint swelling was measured and histological scores of inflammation, synovial thickness, cartilage, and bone destruction were determined. Immunohistochemistry was performed to detect osteoclast and osteoclast precursor FRβ-expressing macrophages and cathepsin K-positive cells on day 21.ResultsIntra-articular administration of the immunotoxin attenuated joint swelling (61% suppression; P < 0.01 compared to the control on day 21) and improved histological findings, particularly cartilage and bone destruction (scores of rats treated with control versus the immunotoxin: 2.2 versus 0.5; P < 0.01), by reducing the number of FRβ-expressing macrophages and cathepsin K-positive cells.ConclusionsIntra-articular administration of an immunotoxin to FRβ is effective for improving rat antigen-induced arthritis.

Evaluation of the novel folate receptor ligand [18F]fluoro-PEG-folate for macrophage targeting in a rat model of arthritis

“…MTX exhibits a relatively low binding affinity for FR, hence more selective targeting of folate antagonists to FR expressing cells in the synovium may be of value if therapy with MTX fails [12]. Other therapy strategies could include folate-immunoconjugates [41] and folate-conjugated vincristine [42]. …”

Novel insights in folate receptors and transporters: implications for disease and treatment of immune diseases and cancer

“…FRβ-positive macrophages were identified in the synovial lining and sublining of RA and OA patients. In a rat arthritis model, FRβ-positive macrophages could be targeted with FRβ antibody-conjugated immunotoxins, leading to reduced joint swelling [96]. Beyond this, these immunotoxins also had a tumor-suppressive effect in a rat C6 glioma tumor xenograft model [97].…”

The Role of Synovial Macrophages in Rheumatoid Arthritis and Osteoarthritis: Its Implications for Radiosynovectomy

“…There is a good deal of recent literature on macrophages in RA, and the potential to induce macrophage apoptosis, to deplete synovial macrophages, or to change the macrophage polarisation from a M1 (classical, infl ammatory) to M2 (alternative, anti-infl ammatory) [ 39 -41 ]. It has been demonstrated that RA synovial lining macrophages express folate receptor-β, and there has been an interest in targeting this to administer either folate antagonists [ 42 ] or an immunotoxin reducing the number of macrophages and inducing benefi t in an animal model of arthritis [ 43 ].…”