Targeting GM-CSF in rheumatoid arthritis A.B. Avci1, E. Feist2, G.R. Burmester2 1Department of Internal Medicine, ABSTRACT well-known as a haemopoietic growth Rheumatology, Akdeniz University, Granulocyte-macrophage colony-stim- factor used to treat neutropenia follow- Faculty of Medicine, Antalya, Turkey; ulating factor (GM-CSF) is well-known ing chemotherapy. It was a long-time 2Department of Rheumatology and as a haemopoietic growth factor. How- concern that targeted therapies against Clinical Immunology, Charite-University Medicine Berlin, Berlin, Germany. ever, it is also essential in regulating this cytokine could cause severe side functions of mature myeloid cells such effects such as neutropenia or pulmo- Ali Berkant Avci, MD, Assoc. Prof. Eugen Feist, PD Dr as macrophages. Preclinical studies nary alveolar proteinosis. Therefore, Gerd-Rüdiger Burmester, Prof. Dr. and observations of flares of arthritis in during the early development phase Please address correspondence to: patients following GM-CSF treatment of compounds targeting GM-CSF or Ali Berkant Avci, MD, supported its important contribution to its receptor special attention was paid Akdeniz Üniversitesi Hastanesi, the pathogenesis of rheumatoid arthritis to this potential adverse event reveal- İç Hastalıkları AD Romatoloji BD, (RA). As the most advanced compound, ing no evidence for such an associated Kampüs 07059 Konyaaltı/Antalya, mavrilimumab, a monoclonal antibody risk profile. On the other hand the so Turkey. against GM-CSF receptor, has already far available results clearly showed E-mail:[email protected] completed phase II trials with a long rapid and sustained effects on disease Received and accepted on June 29, 2016. term of follow-up period of 74 weeks. activity and patient reported outcomes Clin Exp Rheumatol 2016; 34 (Suppl. 98): During this exposure period, an accept- in RA (2). S39-S44. able sustained safety and tolerability © Copyright CLINICAL AND profile has been observed addressing GM-CSF EXPERIMENTAL RHEUMATOLOGY 2016. the concerns of development of cytope- GM-CSF, a small secreted cytokine is nias or pulmonary alveolar proteinosis. a haemopoietic growth factor responsi- Key words: rheumatoid arthritis, Of note, a rapid and sustained efficacy ble for proliferation and differentiation GM-CSF, mavrilimumab, MOR103, and normalisation of acute phase reac- of myeloid cells from bone marrow namilumab tants were consistently shown in studies progenitors. Besides myeloid cells, T both targeting GM-CSF and its recep- and B cells and tissue resident cells in- tor. Its tumour necrosis factor (TNF) cluding chondrocytes, fibroblasts, oste- independent mode of action with con- oblasts, microglia, endothelial and epi- current blockade of GM-CSF as well as thelial cells can secrete GM-CSF (3-5). IL-17 signalling reported from preclini- GM-CSF binds to a heterodimeric GM- cal studies supports the assumption that CSF receptor (GM-CSFR) composed it can be a useful biologic and an alter- of a specific-ligand binding α-chain native agent in TNF inhibitor resistant (GM-CSFRα) and a signal-transducing patients with RA. Therefore, subsequent β-chain (GM-CSFRβ), which is shared studies are warranted to investigate the with IL-3 and IL-5 receptors (6, 7). safety and efficacy of GM-CSF blocking GM-CSFR activation leads to down- agents in different subgroups of RA. stream signalling pathways of Janus kinase-signal transducer and activator Introduction of transcription-suppressor of cytokine Although treatment of rheumatoid ar- signalling (JAK-STAT-SOCS) as well thritis (RA) has evolved tremendously as other pathways including mitogen- in recent years, still an important num- activated protein kinases (MAPK), ber of patients fail to reach the target, phosphatidylinositol 3 kinase (PI3K), disease remission or low disease activ- and NFκB (7-11). The cytoplasmic tail ity (LDA) (1). Blockade of any single of GM-CSFRα has also the capacity to cytokine or cellular subset cannot con- interact with signalling pathways (12). trol the disease in all patients, which GM-CSF is not solely a growth factor necessitates investigations of other cy- responsible for proliferation of mye- Competing interests: G.R. Burmester has tokines or cellular mechanisms respon- loid cells, but also essential in regulat- received honoraria for consulting from sible from RA pathogenesis. To most ing functions of mature myeloid cells MedImmune and GSK; the other authors clinicians, granulocyte-macrophage such as chemotaxis and cell adhesion, have declared no competing interest. colony-stimulating factor (GM-CSF) is dendritic cell function, expression of S-39 GM-CSF in rheumatoid arthritis / A.B. Avci et al. pro-inflammatory cytokines, phago- cytosis, and microbial killing (6, 13, 14). It has a central role in regulating innate immunity. Regarding in vitro studies, GM-CSF can polarise mac- rophages into M1-like macrophages producing inflammatory cytokines in- stead of M2-like macrophages which in contrast produce an anti-inflamma- tory medium (15, 16). However, in vivo studies suggested also association with M2 polarisation in the lung and collaboration of other immune factors such as interferon-gamma (IFNγ), in- terferon regulatory factor 5 (IRF-5) or transforming growth factor-β (TGFβ) family member activin A (17-20). In the pulmonary mucosa, the epithelium is a major producer of GM-CSF. This Fig. 1. GM-CSF as a therapeutic target for inflammation. GM-CSF, is a haemopoietic growth factor re- GM-CSF plays a critical role locally sponsible for proliferation and differentiation of myeloid cells from bone marrow progenitors. Myeloid in regulating microbial defense and cells, T and B cells and tissue resident cells can secrete GM-CSF. GM-CSF can polarise macrophages into M1-like macrophages producing inflammatory cytokines. These cytokines induce the recruitment surfactant clearance by alveolar mac- of inflammatory cells and activation of tissue resident cells. GM-CSF secreted by M1 macrophages rophage population. Defects in GM- induces antigen presenting cells to produce IL-6 and IL-23. IL6 and IL-23 causes again activation of T CSF or its receptor led to death of mice cells and differentiation to TH17 cells which in turn secrete GM-CSF and IL-17 maintaining the circle. GM-CSF produced by TH17cells also induce inflammation by activating monocyte-macrophage system causing pulmonary disease character- and neutrophils. ised by accumulation of surfactant-like APC: antigen presenting cell; DC: dendritic cell; IL: interleukin; G-CSF: granulocyte colony-stimulat- proteins and increased susceptibility to ing factor; GM-CSF: granulocyte-macrophage colony-stimulating factor; TH17: T-helper-17cell; TNF: microbial infection (21). However, a tumour necrosis factor; TRC: tissue resident cell. surprising finding in this study was a relatively normal myelopoiesis. In animal models of arthritis, while de- vrilimumab in adult onset RA patients ficiency and blockade of GM-CSF is with a Disease Activity Score 28-joint GM-CSF and RA protective, overexpression or injection assessment (DAS28) ≤4.8 (mild to GM-CSF is expressed in the synovial of GM-CSF is associated with flares of moderate RA) under a stable dosage membrane and levels of GM-CSF are arthritis (31-35). Other in vitro studies of methotrexate (MTX) for ≥3 months elevated in synovial fluid of RA pa- suggest a role for GM-CSF pathway (43). This was a double-blind placebo- tients (22, 23). The GM-CSFRα is also blockade in tumour necrosis factor controlled study with a 5:1 randomisa- up-regulated in synovial tissue and on (TNF) inhibitor resistant situations and tion (mavrilimumab:placebo) where circulating mononuclear cells from as a part of combinations strategies e.g. patients received single escalating in- RA subjects (24, 25). Synovial tissue with IL-17 or p38 inhibitors (32, 36- travenous (IV) doses of mavrilimumab macrophage populations are associated 39). Finally, the observation of flares (0.01, 0.03, 0.1, 0.3, 1.0, 3.0 and 10.0 with articular damage and decrease in of arthritis following administration of mg/kg) or placebo on study Day 0 and numbers of macrophages is a sensitive recombinant GM-CSF to treat neutro- were followed up for 24 weeks. Over- biomarker for response to treatment in penia in patients with Felty’s syndrome all, 32 patients were enrolled and com- patients with RA (26-28). Since GM- or after chemotherapy suggested a po- pleted the planned evaluations includ- CSF plays a central role in macrophage tential role for targeting GM-CSF and ing safety analysis. The primary objec- differentiation, survival and activation, its receptors in RA (40-42). tive was safety of the compound, while inhibiting GM-CSF activity can affect secondary objectives included pharma- macrophage function and may provide Clinical studies cokinetics and effect on disease activ- clinical benefit in RA. Th17 cells have GM-CSFR inhibition ity. As a surrogate marker for biologic an important place also in RA patho- Phase I. Mavrilimumab (CAM-3001) activity, inhibition of the induction genesis and GM-CSF contributes to is a high-affinity human monoclonal of SOCS3 mRNA by GM-CSF was the differentiation and pathogenicity of antibody to the GM-CSFRα chain shown with doses of 1.0 mg/kg just these cells (29, 30). Figure 1 provides a with competitive antagonistic effect after 4 hours of dosing and this effect schematic representation summarising on GM-CSF signalling. The first in- was sustained over 2 weeks. Of note, the association of GM-CSF with cells human study targeting