Science

We are leveraging more than 30 years of research by our scientific co-founders uncovering the pathobiology of S100A4 – a Damage Associated Molecular Pattern protein upregulated upon stress or injury allowing cells to sense and react to danger. In chronically diseased tissue, S100A4 is inappropriately activated which leads to persistent inflammation and fibrogenesis. Our lead candidate AX-202 is a high-affinity monoclonal antibody neutralizing the bioactivity of S100A4.

About AX-202

A highly differentiated first-in-class monoclonal antibody.
By neutralizing the bioactivity of S100A4, AX-202 confers powerful, yet disease-specific, modulation of multiple independent pathways inappropriately activated in chronic inflammation and tissue fibrosis. AX-202 has been shown to effectively ameliorate tissue fibrosis, chronic inflammation and cancer spread in multiple in vivo models.

About the Target

S100A4 is a Damage Associated Molecular Pattern protein located inside the cells under physiological conditions. Upon tissue injury or stress, S100A4 is released into the extracellular environment alerting the surrounding cells to danger by engaging with Pattern Recognition Receptors. These receptors in turn trigger a broad repertoire of inflammatory and fibrotic responses including release of inflammatory mediators from macrophages and other immune cells, activation and differentiation of fibroblasts, and attraction of additional immune and stromal cells to the site of injury. In chronically diseased tissue, S100A4 is inappropriately upregulated which switches self-limiting tissue repair responses into chronic activation of inflammatory signaling pathways and sustained fibrogenesis. Elevated levels of S100A4 are a hallmark of pathological tissue fibrosis and chronic inflammation and is seen in a wide range of diseases such as systemic sclerosis, idiopathic pulmonary fibrosis, liver cirrhosis, dermatomyositis, psoriasis, rheumatoid arthritis and metastatic cancer.

How our approach is different

Fibrosis is an important cause of disability and mortality globally. It also represents a formidable challenge for scientists and physicians attempting to develop effective treatments. This is because inflammation and extracellular matrix formation, the underlying drivers of fibrosis, both are essential mechanisms by which the body responds to injury and heals. An effective and safe therapy needs to address pathological inflammation and extracellular matrix production without interfering with physiological wound healing and matrix turnover. Many drug candidates have failed to find this balance. Some drugs have shown promising efficacy accompanied by unacceptable side effects. Other drugs have simply proven to be ineffective, even if they were well tolerated. An additional challenge is that as fibrosis progresses, it decouples from inflammation and is sustained in a self-amplifying feedback loop. Drugs that primarily block inflammation thus may show promising effects pre-clinically in animal models of inflammatory-driven fibrosis, but fail to demonstrate meaningful benefit in patients.
Our lead candidate AX-202 represents a novel approach to tackle fibrosis. S100A4, the protein neutralized by AX-202, acts as an upstream, chronic amplifier in the diseased fibrotic tissue microenvironment. By targeting S100A4, AX-202 modifies the dysregulated pathways fueling persistent fibrinogenesis, without interfering with constitutive matrix turnover. Mice with absence of S100A4 display normal organ architecture, but are protected from fibrosis triggered by bleomycin or fibrillin-1 overexpression (tight skin-1). Furthermore, knockdown of S100A4 inhibits the TGFβ driven activation of fibroblasts without impacting TGFβ target genes in resting fibroblasts. Thus, we believe that AX-202 has the potential to address non-resolving tissue fibrosis in a disease-specific and targeted fashion.

Publications

List of selected publications

Neutralization of S100A4 induces stabilization of atherosclerotic plaques: role of smooth muscle cells.
Sakic A, Chaabane C, Ambartsumian N, Klingelhöfer J, Lemeille S, Kwak BR, Grigorian M, Bochaton-Piallat ML.
Cardiovasc Res. 2020 Nov 2:cvaa311. doi: 10.1093/cvr/cvaa311.

 

Anti-S100A4 Antibody Therapy Is Efficient in Treating Aggressive Prostate Cancer and Reversing Immunosuppression: Serum and Biopsy S100A4 as a Clinical Predictor.
Ganaie AA, Mansini AP, Hussain T, Rao A, Siddique HR, Shabaneh A, Ferrari MG, Murugan P, Klingelhöfer J, Wang J, Ambartsumian N, Warlick CA, Konety BR, Saleem M.
Mol Cancer Ther. 2020 Dec;19(12):2598-2611. doi: 10.1158/1535-7163.MCT-20-0410.

 

Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides.
Neidhart M, Pajak A, Laskari K, Riksen NP, Joosten LAB, Netea MG, Lutgens E, Stroes ESG, Ciurea A, Distler O, Grigorian M, Karouzakis E.
Front Immunol. 2019 Apr 15;10:791. doi: 10.3389/fimmu.2019.00791.

 

S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis.
Tomcik M, Palumbo-Zerr K, Zerr P, Avouac J, Dees C, Sumova B, Distler A, Beyer C, Cerezo LA, Becvar R, Distler O, Grigorian M, Schett G, Senolt L, Distler JH.
Ann Rheum Dis. 2015 Sep;74(9):1748-55. doi: 10.1136/annrheumdis-2013-204516.

 

S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance.
Grum-Schwensen B, Klingelhöfer J, Beck M, Bonefeld CM, Hamerlik P, Guldberg P, Grigorian M, Lukanidin E, Ambartsumian N.
BMC Cancer. 2015 Feb 12;15:44. doi: 10.1186/s12885-015-1034-2.

 

A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4.
Hansen MT, Forst B, Cremers N, Quagliata L, Ambartsumian N, Grum-Schwensen B, Klingelhöfer J, Abdul-Al A, Herrmann P, Osterland M, Stein U, Nielsen GH, Scherer PE, Lukanidin E, Sleeman JP, Grigorian M.
Oncogene. 2015 Jan 22;34(4):424-35. doi: 10.1038/onc.2013.568.

 

A generally applicable translational strategy identifies S100A4 as a candidate gene in allergy.
Bruhn S, Fang Y, Barrenäs F, Gustafsson M, Zhang H, Konstantinell A, Krönke A, Sönnichsen B, Bresnick A, Dulyaninova N, Wang H, Zhao Y, Klingelhöfer J, Ambartsumian N, Beck MK, Nestor C, Bona E, Xiang Z, Benson M.
Sci Transl Med. 2014 Jan 8;6(218):218ra4. doi: 10.1126/scitranslmed.3007410.

 

Anti-S100A4 antibody suppresses metastasis formation by blocking stroma cell invasion.
Klingelhöfer J, Grum-Schwensen B, Beck MK, Knudsen RS, Grigorian M, Lukanidin E, Ambartsumian N.
Neoplasia. 2012 Dec;14(12):1260-8. doi: 10.1593/neo.121554.

 

The metastasis promoting protein S100A4 is increased in idiopathic inflammatory myopathies.
Cerezo LA, Kuncová K, Mann H, Tomcík M, Zámecník J, Lukanidin E, Neidhart M, Gay S, Grigorian M, Vencovsky J, Senolt L.
Rheumatology (Oxford). 2011 Oct;50(10):1766-72. doi: 10.1093/rheumatology/ker218.

 

Significance of the S100A4 protein in psoriasis.
Zibert JR, Skov L, Thyssen JP, Jacobsen GK, Grigorian M.
J Invest Dermatol. 2010 Jan;130(1):150-60. doi: 10.1038/jid.2009.206.

 

Metastasis-inducing S100A4 protein is associated with the disease activity of rheumatoid arthritis.
Oslejsková L, Grigorian M, Hulejová H, Vencovsky J, Pavelka K, Klingelhöfer J, Gay S, Neidhart M, Brabcová H, Suchy D, Senolt L.
Rheumatology (Oxford). 2009 Dec;48(12):1590-4. doi: 10.1093/rheumatology/kep316.

Get in touch

    We are dedicated to developing transformative therapies for patients with fibrotic disease.
    We believe that AX-202 has the potential to transform how fibrosis is treated and help many patients poorly served by current therapeutic options.
    Arxx Therapeutics
    in Norway: Gaustadalléen 21, 0349 Oslo
    in Denmark: Symbion Science Park, Fruebjergvej 3, 2100 Copenhagen 
    © 2021 Arxx Therapeutics. All rights reserved. | Privacy Policy