GM-CSF: Autoimmune Disease Drug Target in Cytokines & Growth factors

Introduction of GM-CSF as a Cytokine

Granulocyte-macrophage colony-stimulating factor (GM-CSF) can be viewed as a proinflammatory cytokine rather than as a key regulator of steady state and systemic myelopoiesis. GM-CSF is crucial for the maturation of alveolar macrophages, invariant NK T cells, an intestinal lamina propria DC population and CD103+ dermal DCs. GM-CSF has also been proposed to drive differentiation/activation of murine CD8+ spleen DCs and human plasmacytoid DCs, and to act as the principal CD8+ T cell derived ‘licensing factor’ for murine DC activation involving the upregulation of several co-stimulatory molecules, which positively affects T cell proliferation. GM-CSF circulates at relatively low levels although its levels can rise quite dramatically during immune or inflammatory responses. To what extent GM-CSF is controlling cell numbers, as a pro-survival factor or mitogen, versus controlling cell functions, as an activation/differentiation factor, still needs to be clarified.

Drug Target GM-CSF in Autoimmune Disease

Recent evidence revealed that GM-CSF played critical roles in the development of many autoimmune diseases. GM-CSF depletion or neutralization suppresses many autoimmune disease models, including EAE, arthritis, arthritis-related interstitial lung disease, nephritis, or psoriasis. On the other hand, GM-CSF administration is reported to improve the models of myasthenia gravis, type 1 diabetes, or colitis.
The concentrations of GM-CSF and the number of GM-CSF-producing CD4 T cells in the cerebrospinal fluid were reported to be elevated in MS patients. GM-CSF deficiency or neutralization was reported to prevent the onset of EAE. In contrast, the administration of recombinant GM-CSF exacerbated EAE. In arthritis patients, the concentration of GM-CSF in the synovial fluid and plasma was elevated and the administration of recombinant GM-CSF exacerbated the disease activity. Higher levels of GM-CSF secretion have been detected in mucosal lesions of inflammatory bowel disease (IBD) compared with normal mucosa and also in the colon lesions of dextran sodium (DSS)-induced colitis mice model. On the other hand, in Crohn's disease, the increased levels of GM-CSF autoantibodies have been reported.

Targeting GM-CSF for Autoimmune Disease Therapy

There are several ongoing or completed clinical trials targeting GM-CSF or GM-CSF receptor. Although GM-CSF inhibition showed rapid clinical response with no serious adverse reactions so far, there are some potential side effects which need to be monitored.


Mavrilimumab is a human monoclonal antibody against GM-CSF receptor α. In the first phase 1 study, 32 subjects with mild arthritis received single intravenous escalating doses of mavrilimumab and showed its safety and tolerability.


MOR103, which is a fully human monoclonal antibody against GM-CSF, has shown preliminary evidence of safety and rapid efficacy (within 2 weeks) in a randomized, double-blind, placebo-controlled, dose-escalating phase 1b/2a trial for patients with moderate arthritis (n=96).


Namilumab is a human monoclonal antibody against GM-CSF. In a randomized, double-blind, dose-escalating phase 1b study, mild to moderate RA patients received three times of every 2-week injection of namilumab and showed its safety and tolerability.


KB003 is a humanized monoclonal antibody targeting GM-CSF. A randomized phase 2 study in RA patients showed safety and tolerability in 3 months of repeated dosing.


MORAb-002 is a human monoclonal antibody against GM-CSF. A randomized, double-blind phase 1 trial in RA was completed recently.

GM-CSF as Drug Target in Autoimmune Disease: Conclusion

Recent studies clarified the pivotal roles of GM-CSF in the development of many autoimmune diseases. Much attention has been focused on the inhibition of GM-CSF as an attractive approach for the treatment of these diseases. Further studies to clarify the molecular mechanism of GM-CSF production and precise role of GM-CSF in the development of autoimmune disease are awaited with interest.