Involution of Collagen-Induced Arthritis with an Angiogenesis Inhibitor, PPI-2458

Abstract

Pannus formation, in both rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), is angiogenesis-dependent. PPI-2458 [(1R)-1-carbamoyl-2-methyl]-carbamic acid-(3R,3S,5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)oxiranyl]-1-oxaspiro(2*5)oct-6-yl ester], a new fumagillin derivative known to inhibit methionine aminopeptidase 2 (MetAP-2) and endothelial proliferation at the late G 1 phase, was evaluated in CIA rats to study its potential to involute synovitis. Arthritic syngeneic LOU rats received either a vehicle control or various dosages of oral, intravenous, or subcutaneous PPI-2458. Plasma samples were analyzed to determine a pharmacokinetic profile of PPI-2458, and whole blood was evaluated by flow cytometry to assess the effect on lymphocyte subsets. At 15 mg/kg i.v., 30 mg/kg s.c., or 100 mg/kg p.o., there was a significant reduction in clinical severity scores (p Ͻ 0.001) and blinded radiographic scores (p Ͻ 0.001) compared with vehicle control groups. Structural damage was virtually eliminated with PPI-2458. Continuous inhibition of MetAP-2 was needed to maintain benefits, although pannus involution could be achieved with the inhibitor when escape flares occurred. Pharmacokinetic analysis after a single p.o. dose showed a rapid T max value of 15 min followed by biphasic elimination (t 1 ⁄2, ϳ20 min and t 1 ⁄2, ϳ5 h) and an estimated oral bioavailability of ϳ15%. Flow cytometry revealed a dosedependent decrease in white blood cells and lymphocytes manifested as decreases in circulating CD3ϩ T cells and natural killer cells. PPI-2458, however, did not seem to be immunosuppressive, as determined by delayed-type hypersensitivity or IgG antibody assays. These studies indicate that the MetAP-2 inhibitor PPI-2458 can regress established CIA and that angiogenic mechanisms might be important targets in the treatment of other pannus-mediated diseases such as RA.Angiogenesis, or new blood vessel formation, is limited in nondisease states to embryogenesis/growth, wound healing, and menstrual cycles. Pathologic angiogenesis is observed in more than 70 diseases, including cancer, proliferative retinopathy, and pannus formation in rheumatoid arthritis (RA) (Carmeliet, 2005;Lainer and Brahn, 2005;Lainer-Carr and Brahn, 2007).The synovium in healthy joints is relatively thin. It contains macrophage-like type A cells that produce degradative enzymes and fibroblast-like type B cells that are responsible for synovial fluid production. The synovium normally does not encroach upon the articular surface of cartilage. The subsynovial tissue is distinct from the synovial lining layer and contains lymphatics and blood vessels as well as fibroblasts and adipocytes.

An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis

“…It was previously demonstrated that PPI-2458 has protective effects on joint swelling in the rat models of arthritis induced by collagen or PG-PS [24,28,34]. Here we expand on that work, determining how the protective effects of MetAP-2 inhibition relate to the temporal development of the multistage PG-PS model of arthritis and further elucidating a mechanistic role for MetAP-2 in the pathophysiological processes involved in joint destruction of rat experimental models of arthritis.…”

“…Antiangiogenic agents that can stem pannus formation by effectively blocking the development of a blood supply have found success in experimental models of arthritis [12,28,29]. PPI-2458 is one such antiangiogenic agent that is an orally active irreversible inhibitor of the enzyme methionine aminopeptidase type-2 (MetAP-2).…”

“…PPI-2458 and another fumagillin analog, TNP-470, are protective in the rat model of collagen-induced arthritis [12,28,34]. It was previously demonstrated that PPI-2458 has protective effects on joint swelling in the rat models of arthritis induced by collagen or PG-PS [24,28,34].…”

Angiogenesis and the persistence of inflammation in a rat model of proliferative synovitis

“…This triggers growth arrest of ECs in the late G 1 phase of the cell cycle, inhibiting EC proliferation and angiogenesis without affecting inflammatory cytokine release (19,21,22) or inducing apoptosis in ECs (23). PPI-2458 has reduced toxicity and greater selectivity for angiogenesis inhibition versus inflammation as compared with another fumagillin analog, AGM-1470/TNP-470 (23,24).…”

Metabolites of PPI-2458, a Selective, Irreversible Inhibitor of Methionine Aminopeptidase-2: Structure Determination and In Vivo Activity

“…PPI-2458, [(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-enyl) oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl] N-[(2R)-1-amino-3-methyl-1-oxobutan-2-yl]carbamate, differs from fumagillin in that the polyolefinic chain is replaced by a carbamoyl-linked D-valinamide moiety (Olson et al, 2003;Arico-Muendel et al, 2009). PPI-2458 has demonstrated efficacy in rodent models for non-Hodgkin lymphoma (Cooper et al, 2006), melanoma , and arthritis (Bernier et al, 2004;Bainbridge et al, 2007;Hannig et al, 2007;Lazarus et al, 2008;Brahn et al, 2009;Ashraf et al, 2010;Ashraf et al, 2011). In preclinical studies, PPI-2458 was approximately equipotent in several in vivo efficacy models by both oral and parenteral routes of administration, despite an apparently modest oral bioavailability (F% = 6) (AricoMuendel et al, 2009).…”