Clinical Information

Granulocyte macrophage-colony stimulating factor (GM-CSF) was initially characterized as a hematopoietic growth factor, acting on bone marrow progenitor and inducing differentiation and proliferation of myeloid cells.(1) GM-CSF gene-deficient mice, however, displayed no changes in steady state myelopoiesis. In contrast, the predominant phenotype of the GM-CSF knock-out mouse was similar to that of human pulmonary alveolar proteinosis (PAP), a condition which is characterized by an accumulation of pulmonary surfactant.(2) Subsequently, it was observed that approximately 90% of human PAP, referred to as autoimmune PAP, is associated with autoantibodies specific for GM-CSF.(3) Taken together, evidence from mice and humans point to a critical role for GM-CSF in maintenance of proper alveolar macrophage function.

GM-CSF has also been shown to play an important role in the regulation of innate and adaptive immune responses. These observations led to additional studies probing the role of this molecule in chronic inflammatory and autoimmune diseases. One of the first studies in this area demonstrated that patients with severe and moderate rheumatoid arthritis (RA) had plasma GM-CSF concentrations that were significantly elevated compared to healthy controls.(5) In addition, treatment of patients with Felty syndrome and RA with GM-CSF, which was administered in an attempt to increase neutrophil counts, led to exacerbation of the inflammatory arthritis.(6) In a recent study, elevated serum concentrations of GM-CSF were detected in patients with radiographic axial spondyloarthropathy (SpA) compared to controls, and concentrations of this cytokine correlated with disease activity score.(7)

It is now well accepted that GM-CSF plays a role in the pathology of a variety of chronic inflammatory diseases and, as such, is a viable therapeutic target.(9) There are currently 4 monoclonal antibodies targeting the GM-CSF pathway.(8) One of the first, mavrilimumab, is specific for the alpha-chain of the GM-CSF receptor. Two phase IIb clinical trials in RA showed significant improvements in disease activity compared to placebo without any significant side effects or adverse events. Improvements were rapid (within 2 weeks) and dose dependent. The remaining 3 biologics, otilimab, namilumab, and lenzilumab, target GM-CSF directly. Several phase II clinical trials of namilumab in RA and plaque psoriasis have been completed, and a phase IIa trial in axial spondyloarthropathy is currently recruiting. Otilimab is being evaluated in 2 phase II clinical trials specifically targeting RA patients who have shown poor response to disease-modifying antirheumatic drugs or other treatments. Lenzilumab is currently being evaluated as a novel therapeutic in asthma.