Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra

Joosten, Leo A. B.; Crişan, Tania O.; Azam, Tania; Cleophas, Maartje C. P.; Koenders, Marije I.; Veerdonk, Frank L. van de; Netea, Mihai G.; Kim, Soohyun; Dinarello, Charles A.

doi:10.1136/annrheumdis-2014-206966

Cited by 62 publications

(41 citation statements)

References 45 publications

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“…In addition, AAT possesses a broad spectrum of anti-inflammatory (37,39) and immunomodulatory properties, unrelated to protease inhibition (37,40), including elevation of cAMP in target cells (41) and inhibition of the aggrecanase ADAMTS-4 (42). A recent study reported the antiarthritic properties of an ATT-Fc fusion protein in murine acute gouty arthritis with reduced release of IL-1b and induction of IL-1 receptor antagonist (43). Equally pertinent is the observation that AAT treatment reduces autoimmunity and delays arthritis development in a mouse model of collagen-induced arthritis (44).…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates

Kaneva

Greco

Headland

et al. 2017

The Journal of Immunology

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We hypothesized that exudates collected at the beginning of the resolution phase of inflammation might be enriched for tissue protective molecules; thus an integrated cellular and molecular approach was applied to identify novel chondroprotective bioactions. Exudates were collected 6 h (inflammatory) and 24 h (resolving) following carrageenan-induced pleurisy in rats. The resolving exudate was subjected to gel filtration chromatography followed by proteomics, identifying 61 proteins. Fractions were added to C28/I2 chondrocytes, grown in micromasses, ions with or without IL-1β or osteoarthritic synovial fluids for 48 h. Three proteins were selected from the proteomic analysis, α1-antitrypsin (AAT), hemopexin (HX), and gelsolin (GSN), and tested against catabolic stimulation for their effects on glycosaminoglycan deposition as assessed by Alcian blue staining, and gene expression of key anabolic proteins by real-time PCR. In an in vivo model of inflammatory arthritis, cartilage integrity was determined histologically 48 h after intra-articular injection of AAT or GSN. The resolving exudate displayed protective activities on chondrocytes, using multiple readouts: these effects were retained in low m.w. fractions of the exudate (46.7% increase in glycosaminoglycan deposition; ∼20% upregulation of COL2A1 and aggrecan mRNA expression), which reversed the effect of IL-1β. Exogenous administration of HX, GSN, or AAT abrogated the effects of IL-1β and osteoarthritic synovial fluids on anabolic gene expression and increased glycosaminoglycan deposition. Intra-articular injection of AAT or GSN protected cartilage integrity in mice with inflammatory arthritis. In summary, the strategy for identification of novel chondroprotective activities in resolving exudates identified HX, GSN and AAT as potential leads for new drug discovery programs.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates

Kaneva

Greco

Headland

et al. 2017

The Journal of Immunology

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“…Gout arthritis was induced in mice through i.a. injection of MSU and palmitate (C16) as previously described (43,44). Hyperuricemia was induced in mice through uricase inhibition with oxonic acid (45,46).…”

Section: Methodsmentioning

confidence: 99%

Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway

Crişan

Cleophas

Novakovic

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

113

105

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Metabolic triggers are important inducers of the inflammatory processes in gout. Whereas the high serum urate levels observed in patients with gout predispose them to the formation of monosodium urate (MSU) crystals, soluble urate also primes for inflammatory signals in cells responding to gout-related stimuli, but also in other common metabolic diseases. In this study, we investigated the mechanisms through which uric acid selectively lowers human blood monocyte production of the natural inhibitor IL-1 receptor antagonist (IL-1Ra) and shifts production toward the highly inflammatory IL-1β. Monocytes from healthy volunteers were first primed with uric acid for 24 h and then subjected to stimulation with lipopolysaccharide (LPS) in the presence or absence of MSU. Transcriptomic analysis revealed broad inflammatory pathways associated with uric acid priming, with NF-κB and mammalian target of rapamycin (mTOR) signaling strongly increased. Functional validation did not identify NF-κB or AMP-activated protein kinase phosphorylation, but uric acid priming induced phosphorylation of AKT and proline-rich AKT substrate 40 kDa (PRAS 40), which in turn activated mTOR. Subsequently, Western blot for the autophagic structure LC3-I and LC3-II (microtubule-associated protein 1A/1B-light chain 3) fractions, as well as fluorescence microscopy of LC3-GFPoverexpressing HeLa cells, revealed lower autophagic activity in cells exposed to uric acid compared with control conditions. Interestingly, reactive oxygen species production was diminished by uric acid priming. Thus, the Akt-PRAS40 pathway is activated by uric acid, which inhibits autophagy and recapitulates the uric acid-induced proinflammatory cytokine phenotype.uric acid | interleukin-1 | interleukin-1 receptor antagonist | AKT | autophagy

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“…In 2013, such a patent application was issued describing the production of Fc-fusion recombinant AAT molecule, later also mentioned to have superior serum half-life to the wild-type version of the protein, while still retaining its anti-inflammatory properties. [54] …”

Section: Patents On Aat Productionmentioning

confidence: 97%

“…[27,31,73] The first patent to describe the use of AAT for the treatment of bacterial infection was published in 2005, [74] describing the administration of AAT as a means of protection from and treatment of mycobacterial infection. On this ground, one patent application was published in 2012 and two in 2014, all of which describe the construct of an AAT-Fc fusion molecule, already known to be anti-inflammatory and cytoprotective, [43,44,54] to treat and prevent mycobacterial infection.…”

Section: Patents On Reduction Of Bacterial Burdenmentioning

confidence: 98%

Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

Lior

Geyra²,

Lewis

2016

Expert Opinion on Therapeutic Patents

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A molecule no longer patentable per se, presents with novel clinical applications; its mechanism still unfolding. While modified protein sequences are patentable and potentially superior, they are burdened by regulatory setbacks. Thus, recent approaches in the context of AAT appear in patents that describe combinations with other drugs, redefined clinical subclasses, and unique recombinant entities, carefully skirting saturated areas of AAT patentology. It will be fascinating to follow technologies and creative patenting as AAT navigates the trying trades of pharmaceutical industry towards an increasing lineup of unmet clinical needs.

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Alpha-1-anti-trypsin-Fc fusion protein ameliorates gouty arthritis by reducing release and extracellular processing of IL-1β and by the induction of endogenous IL-1Ra

Abstract: A single low dose of AAT-Fc is highly effective in reducing joint inflammation in this model of acute gouty arthritis. Considering the long-term safety of plasma-derived AAT use in humans, subcutaneous AAT-Fc emerges as a promising therapy for gout attacks.

Cited by 62 publications

References 45 publications

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates

Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway

Therapeutic compositions and uses of alpha1-antitrypsin: a patent review (2012 – 2015)

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