Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as CSF2, is a cytokine with a well-established role in hematopoiesis and a growing presence in inflammatory disease research.
Initially recognized for its ability to support the production and function of myeloid cells, GM-CSF is now being investigated across a broader range of disease settings. Both enhancing and inhibiting GM-CSF signaling have become therapeutic strategies, depending on the underlying disease biology.
Recent clinical developments, particularly in autoimmune pulmonary alveolar proteinosis (aPAP), have renewed interest in this pathway. At the same time, clinical studies targeting GM-CSF or its receptor have highlighted the complexity of modulating this signaling axis.
Why can GM-CSF support hematopoiesis in one context while contributing to inflammation in another? How does this dual role shape its therapeutic potential?
Understanding GM-CSF signaling and its context-dependent effects is key to exploring both the activation and inhibition of this pathway in drug development.
GM-CSF: A Key Regulator of Myeloid Cell Biology
GM-CSF is a monomeric glycoprotein produced by various cell types, including macrophages, T cells, stromal cells, natural killer cells, endothelial cells, and fibroblasts.
Its primary biological functions include regulating the production of granulocytes and monocytes and influencing the differentiation, survival, and activation of myeloid cells.
However, GM-CSF activity is not uniform across biological settings. Its effects depend on several factors, including cytokine concentration, target cell type, and the surrounding tissue microenvironment.
Depending on these conditions, GM-CSF can promote immune cell survival and activation, support myeloid cell differentiation, or contribute to inflammatory responses. This context-dependent activity is an important consideration in understanding its role in both normal physiology and disease.
GM-CSF / GM-CSFR Signaling Pathway
GM-CSF exerts its biological effects by binding to the GM-CSF receptor (GM-CSFR), a heterodimeric receptor complex composed of two subunits:
GM-CSFRα (CSF2RA): The ligand-specific α subunit responsible for GM-CSF binding.
Common β chain (βc, CSF2RB): The signal-transducing subunit, which is also shared by the IL-3 and IL-5 receptor complexes.
Upon ligand binding, GM-CSF first interacts with GM-CSFRα, followed by recruitment of the βc subunit. This process forms a 2:2:2 hexameric signaling complex and initiates downstream signaling, including JAK2 activation.
Dose-dependent signaling responses
One important feature of GM-CSF signaling is its ability to activate different downstream pathways depending on ligand concentration.
At lower GM-CSF concentrations, phosphorylation of Ser585 on the β chain promotes PI3K/Akt signaling and increases BCL-2 activity, supporting cell survival.
At higher concentrations, tyrosine phosphorylation of the β chain activates the JAK2/STAT5 pathway. This can regulate transcription factors such as PU.1, IRF4, and IRF8, contributing to changes in myeloid cell differentiation and function.
The pathway is also subject to negative regulation. Suppressors of cytokine signaling (SOCS) proteins, for example, help limit JAK/STAT activity and prevent sustained signaling.
Another important consideration is receptor sharing. Because GM-CSF, IL-3, and IL-5 use the same βc signaling subunit, their downstream signaling outputs can partially overlap. This shared receptor architecture adds complexity to pathway-specific therapeutic intervention.
Approved GM-CSF-Related Therapies
GM-CSF has already been translated into clinical applications through both cytokine replacement and immunotherapy strategies.
Sargramostim: Recombinant GM-CSF therapy
Sargramostim (Leukine), a recombinant human GM-CSF produced using a yeast expression system, received its first FDA approval in 1991.
In 2018, the FDA also approved sargramostim for the hematopoietic syndrome of acute radiation syndrome (H-ARS) under the Animal Rule, based on efficacy data from animal studies.
This represents an established clinical application of GM-CSF as a hematopoietic growth factor.
GM-CSF as an immunotherapy component
GM-CSF has also been incorporated into certain cancer immunotherapy strategies.
Dinutuximab, an anti-GD2 monoclonal antibody, is used in an approved combination regimen that includes GM-CSF for selected patients with high-risk neuroblastoma.
Another example is talimogene laherparepvec (T-VEC), an oncolytic viral therapy engineered to express GM-CSF. Its design aims to promote local immune activation within the tumor microenvironment.
These applications demonstrate that GM-CSF can serve different roles depending on the therapeutic context, from supporting hematopoietic recovery to contributing to antitumor immune responses.
GM-CSF Drug Development: Two Therapeutic Directions
Current GM-CSF-related drug development broadly follows two approaches: restoring GM-CSF activity when signaling is insufficient, and inhibiting the pathway when excessive myeloid activation contributes to disease.
Restoring GM-CSF signaling: Development in aPAP
Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease characterized by the accumulation of pulmonary surfactant within the alveoli.
In patients with aPAP, autoantibodies neutralize GM-CSF, impairing the function of alveolar macrophages. These cells consequently become less effective at clearing excess surfactant.
Molgramostim, developed by Savara, is an inhaled recombinant human GM-CSF designed to restore GM-CSF activity locally in the lungs.
In the Phase 3 IMPALA-2 study, which enrolled 164 patients, the molgramostim group showed a 9.8-percentage-point improvement in diffusing capacity of the lungs for carbon monoxide (DLCO) from baseline at Week 24, compared with 3.8 percentage points in the placebo group. The between-group difference was 6.0 percentage points (95% CI: 2.5–9.4; P<0.001).
The FDA accepted the Biologics License Application (BLA) for review and granted Priority Review. Following an extension of the review period, the PDUFA target action date was set for November 22, 2026.
If approved, molgramostim could become the first approved pharmacological treatment for aPAP, marking an important development in GM-CSF replacement therapy.
Blocking GM-CSF signaling: Clinical exploration in inflammatory diseases
The second approach aims to inhibit GM-CSF or its receptor to reduce excessive myeloid cell activation and inflammatory responses.
Several monoclonal antibodies have been investigated in this area, although clinical outcomes have varied across indications.
Otilimab, an anti-GM-CSF antibody developed by GSK, was evaluated in Phase 3 studies for rheumatoid arthritis. While some studies met their primary endpoints, the ContRAst-3 study did not. GSK subsequently decided not to proceed with a marketing application.
Namilumab, another anti-GM-CSF antibody, was investigated in chronic pulmonary sarcoidosis. However, the Phase 2 study did not demonstrate the expected clinical benefit.
Mavrilimumab, which targets GM-CSFRα, was explored in giant cell arteritis. Although the Phase 2 study showed encouraging signals, the development and licensing program was subsequently discontinued.
These outcomes illustrate the challenges of translating GM-CSF pathway inhibition into clinical benefit. Differences in disease mechanisms, patient populations, and the degree of pathway involvement may all influence therapeutic responses.
Expanding into acute inflammatory conditions
Beyond chronic inflammatory diseases, GM-CSF inhibition has also been explored in acute inflammatory conditions.
Plonmarlimab (TJM2), an anti-GM-CSF monoclonal antibody developed by I-Mab, has been investigated in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (sHLH), as well as acute gouty arthritis and sepsis-related inflammation.
The development program reflects continued interest in GM-CSF as a potential regulator of excessive inflammatory responses. However, the clinical value of this approach remains to be established through further studies.
GM-CSF inhibition has also been investigated in the context of CAR T-cell therapy-related inflammatory toxicity. Lenzilumab was evaluated in combination with axicabtagene ciloleucel (axi-cel) in the ZUMA-19 study. The study enrolled only six patients, and its planned Phase 2 portion was not conducted. The limited dataset is insufficient to establish clinical benefit.
GM-CSF Research Products from Genomeditech
The complexity of GM-CSF signaling presents several challenges for targeted drug development. Dose-dependent signaling outputs, cytokine crosstalk mediated by the shared βc subunit, and distinct therapeutic strategies involving pathway activation or inhibition all add complexity to in vitro candidate evaluation.
To support these research needs, Genomeditech offers a portfolio of GM-CSF-related research tools, including reporter cell lines, recombinant proteins, and reference antibodies. This integrated product portfolio supports molecular binding studies and cell-based pathway activity evaluation, facilitating the in vitro functional assessment of neutralizing antibodies and pathway agonists.
Explore the available products: https://en.genomeditech.com/v2/search?k=GM-CSF
References
1. Zhan, Y., Lew, A. M., & Chopin, M. (2019). The pleiotropic effects of the GM-CSF rheostat on myeloid cell differentiation and function: More than a numbers game. Frontiers in Immunology, 10, 2679.
https://doi.org/10.3389/fimmu.2019.02679
2. Lee, K. M. C., Achuthan, A. A., & Hamilton, J. A. (2020). GM-CSF: A promising target in inflammation and autoimmunity. ImmunoTargets and Therapy, 9, 225–240.
https://doi.org/10.2147/ITT.S262566
3. van den Blink, B., Birring, S. S., Mogulkoc, N., et al. (2026). Safety and efficacy of namilumab for the treatment of chronic pulmonary sarcoidosis (RESOLVE-Lung): A randomised, double-blinded, multicentre, phase 2 study. European Respiratory Journal, 68(1), 2501874.
https://doi.org/10.1183/13993003.01874-2025
4. Partner Therapeutics. LEUKINE® (sargramostim) Prescribing Information.
https://www.leukine.com/wp-content/uploads/2020/06/Prescribing_Information.pdf
5. U.S. Food and Drug Administration. (2018, March 29). FDA approves Leukine for Acute Radiation Syndrome.
https://www.fda.gov/media/112441/download
6. United Therapeutics. UNITUXIN® (dinutuximab) Full Prescribing Information.
https://unituxin.com/full-prescribing-information.pdf
7. Trapnell, B. C., Inoue, Y., Bonella, F., et al. (2025). Phase 3 trial of inhaled molgramostim in autoimmune pulmonary alveolar proteinosis. The New England Journal of Medicine, 393(8), 764–773.
https://doi.org/10.1056/NEJMoa2410542
8. Trapnell, B. C., Nakata, K., Bonella, F., et al. (2019). Pulmonary alveolar proteinosis. Nature Reviews Disease Primers, 5(1), 16.
https://doi.org/10.1038/s41572-019-0066-3
9. Savara Inc. (2026, April 15). Savara announces the U.S. FDA has extended the review period for the molgramostim BLA in autoimmune PAP.
Read the press release
10. MorphoSys AG. (2022). Management Report and Financial Statements as of December 31, 2022.
View the financial report archive
11. Cid, M. C., Unizony, S. H., Blockmans, D., et al. (2022). Efficacy and safety of mavrilimumab in giant cell arteritis: A phase 2, randomised, double-blind, placebo-controlled trial. Annals of the Rheumatic Diseases, 81(5), 653–661.
https://doi.org/10.1136/annrheumdis-2021-221865
12. Kiniksa Pharmaceuticals International plc. (2025, February 21). Form 8-K: Termination of development of mavrilimumab and related license agreement.
View SEC filing
13. I-Mab (天境生物). Product Pipeline.
https://www.tjbio.com/
14. ClinicalTrials.gov. Study of Lenzilumab and Axicabtagene Ciloleucel in Participants With Relapsed or Refractory Large B-Cell Lymphoma (ZUMA-19). NCT04314843.
https://clinicaltrials.gov/study/NCT04314843
