Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI‐2458

Hannig, Gerhard; Bernier, Sylvie G.; Hoyt, Jennifer; Doyle, Beth; Clark, Edward C.; Karp, Russell; Lorusso, Jeanine; Westlin, William

doi:10.1002/art.22402

Cited by 27 publications

(19 citation statements)

References 40 publications

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“…This study of the metabolism of PPI-2458 was driven by observations of efficacy in animal models for cancer (Cooper et al, 2006;Hannig et al, 2006) and rheumatoid arthritis (Hannig et al, 2007;Lazarus et al, 2008) after oral dosing, despite apparent low oral bioavailability of the parent compound. As a first step toward characterization of PPI-2458 metabolism in vivo, we studied the effects of treatment with liver microsomal preparations.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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The natural product fumagillin exhibits potent antiproliferative and antiangiogenic properties. The semisynthetic analog 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, demonstrates rapid inactivation of its molecular target, methionine aminopeptidase-2 (MetAP2), and good efficacy in several rodent models of cancer and inflammation with oral dosing despite low apparent oral bioavailability. To probe the basis of its in vivo efficacy, the metabolism of PPI-2458 was studied in detail. Reaction phenotyping identified CYP3A4/5 as the major source of metabolism in humans. Six metabolites were isolated from liver microsomes and characterized by mass spectrometry and nuclear resonance spectroscopy, and their structures were confirmed by chemical synthesis. The synthetic metabolites showed correlated inhibition of MetAP2 enzymatic activity and vascular endothelial cell growth. In an ex vivo experiment, MetAP2 inhibition in white blood cells, thymus, and lymph nodes in rats after single dosing with PPI-2458 and the isolated metabolites was found to correlate with the in vitro activity of the individual species. In a phase 1 clinical study, PPI-2458 was administered to patients with non-Hodgkin lymphoma. At 15 mg administered orally every other day, MetAP2 in whole blood was 80% inactivated for up to 48 hours, although the exposure of the parent compound was only ∼10% that of the summed cytochrome P450 metabolites. Taken together, the data confirm the participation of active metabolites in the in vivo efficacy of PPI-2458. The structures define a metabolic pathway for PPI-2458 that is distinct from that of TNP-470 ([(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-(2-chloroacetyl)carbamate). The high level of MetAP2 inhibition achieved in vivo supports the value of fumagillin-derived therapeutics for angiogenic diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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“…Sustained inhibition of angiogenesis that is begun during the induction, or at the onset, of synovitis can reduce inflammation and joint damage (21,23,27,37,38). However, adverse effects of long-term angiogenesis inhibition on physiologic blood vessel growth may outweigh the therapeutic benefit in chronic inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

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

Ashraf

Mapp

Walsh

2010

Arthritis & Rheumatism

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Objective. To determine whether blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence and whether inhibiting this angiogenesis at the onset of persistent inflammation leads to its subsequent resolution.Methods. Inflammation and angiogenesis were induced by injection of 0.03% carrageenan and/or 6 pmoles of fibroblast growth factor 2 (FGF-2) into rat knees. A brief treatment with the angiogenesis inhibitor PPI-2458 (5 mg/kg orally on alternate days) was administered 1 day before and up to 3 days after synovitis induction. Controls comprised naive and vehicle-treated rats. Synovial angiogenesis was measured using the endothelial cell proliferation index, and inflammation was determined by measuring joint swelling and macrophage percentage area. Data are presented as the geometric mean (95% confidence interval).Results. Intraarticular injection of 0.03% carrageenan into rat knees produced acute synovitis, which was not associated with synovial angiogenesis and which resolved within 29 days. Injection of FGF-2 (6 pmoles) induced synovial angiogenesis without significant synovitis. Stimulation of angiogenesis with FGF-2 at the time of carrageenan injection was followed by synovitis that persisted for 29 days. Persistence of carrageenan/FGF-2-induced synovitis was prevented by systemic administration of 3 doses of the angiogenesis inhibitor PPI-2458 during the acute phase.Conclusion. Our findings indicate that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis, and brief antiangiogenic treatment during the acute phase of synovitis may prevent its subsequent progression. Clinical studies will be needed to determine whether brief antiangiogenic treatment may reduce the burden of inflammatory joint diseases such as rheumatoid arthritis by facilitating the resolution of early synovitis.

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“…This is most likely because of PPI-2458 inhibition of human fibroblast-like synoviocyte proliferation (Bernier et al, 2004) in pannus growth and contributes to migration of inflammatory cells from the periphery (Bernier et al, 2005). Furthermore, previous in vitro work has demonstrated that PPI-2458 inhibits osteoclast precursor differentiation into multinucleated osteoclasts (Hannig et al, 2007;Lazarus et al, 2008), possibly by inhibiting fibroblastlike synoviocytes that release receptor activator of nuclear factor-B ligand, which promotes osteoclast formation and activation (Teitelbaum, 2000;Bernier et al, 2004;Wu et al, 2005;Hannig et al, 2007). Such an effect would alter the balance between bone formation and bone resorption (Campagnuolo et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…1) that targets MetAP-2 and inhibits endothelial cell proliferation (Bernier et al, 2005). This compound has been shown to reduce swelling in a peptidoglycan-polysaccharide-induced model when administered subcutaneously or orally (Bernier et al, 2004;Hannig et al, 2007) and to suppress murine collagen-induced arthritis (CIA) (Bainbridge et al, 2007). The current study evaluates PPI-2458 in the rat CIA RA model of autoimmune chronic inflammatory arthritis (Trentham et al, 1977).…”

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confidence: 99%

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

Brahn¹,

Schoettler²,

Lee³

et al. 2009

J Pharmacol Exp Ther

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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.

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Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI‐2458

Cited by 27 publications

References 40 publications

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

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

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

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

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