GM-CSF inhalation therapy: a narrative

By Koh Nakata, representative director of GIPO.
Supervised by Dr. Tomohiro Handa, Associate Professor,
Department of Advanced Medicine for Respiratory Failure,
Graduate School of Medicine, Kyoto University.

Why do anti-GM-CSF autoantibodies cause autoimmune pulmonary alveolar proteinosis?

(GM-CSF is an abbreviation for granulocyte macrophage colony stimulating factor.)

GM-CSF was discovered in the 1970s by Donald Metcalf in Australia, as a protein that promotes the growth of bone marrow cells that differentiate into white blood cells in the blood. GM-CSF was put into practical use as a drug in the 1990s for the purpose of increasing the number of white blood cells in patients with low numbers of white blood cells in their blood after chemotherapy for hematological disorders or cancer. In Japan, a protein called granulocyte colony stimulating factor (G-CSF) was first developed as a drug for the purpose of increasing white blood cell numbers, and the practical application of GM-CSF was delayed.

GM-CSF is produced by various cells in the body

In the lung, "type II epithelial cells" in the alveoli, sac-like tissues that take in oxygen, produce a large amount of GM-CSF. The released GM-CSF binds to a protein called a receptor on the surface of alveolar macrophages, encouraging alveolar macrophages to mature, proliferate, and strengthen their functions. Alveolar macrophages are "cleaner cells" within the alveoli. The air breathed in through the nose and mouth enters the alveoli, so dust and bacteria also enter. Additionally, the surface of the alveoli is covered with a viscous fluid called "surfactant." Alveolar macrophages engulf and digest the foreign and local waste materials, keeping the alveoli clean.

Patients with autoimmune pulmonary alveolar proteinosis have high concentrations of anti- GM-CSF autoantibodies that neutralize GM-CSF. Antibodies are normally produced in lymph nodes to bind and eliminate viruses and bacteria that invade from the outside, but antibodies against oneʼs own tissues or cells may also be produced. These are called "autoantibodies." The act of binding to GM-CSF and rendering it inactive is called "neutralization," and the autoantibodies that neutralize are called "neutralizing autoantibodies."

Anti-GM-CSF neutralizing autoantibodies in patients with autoimmune alveolar proteinosis are found not only in the blood but also in the alveoli. Therefore, it binds to and neutralizes GM-CSF, which is actively released by type II epithelial cells. Alveolar macrophages mature, proliferate, and function when GM-CSF binds to them, so if GM-CSF cannot bind to them, they immediately weaken. The alveoli can no longer be cleaned, and waste products continue to accumulate in the alveoli. This is what occurs in autoimmune pulmonary alveolar proteinosis.

Why is GM-CSF inhalation effective against autoimmune pulmonary alveolar proteinosis?

In 1996, Seymour et al. in Australia attempted to administer GM-CSF by subcutaneous injection to revitalize the weakened alveolar macrophages of patients with pulmonary alveolar proteinosis. The patient's lungs cleared and respiratory function improved. However, all patients treated in this way relapsed, and the treatment was gradually discontinued thereafter. In response, an attempt was made in 1999 by Wylam et al. at the Mayo Clinic in the United States to deliver GM-CSF to the alveoli, through inhalation, in 10 patients with relatively mild symptoms, and all showed improvement in respiratory function.

In Japan, Tazawa, Nukiwa, and colleagues at Tohoku University conducted research on two patients with severe autoimmune pulmonary alveolar proteinosis from 2000 to 2002. When the patients repeated the cycle of inhaling GM-CSF twice in the morning and evening for one week and then desisting for one week, Tazawa confirmed that respiratory failure dramatically improved. GM-CSF inhalation therapy then received research funding from the Ministry of Health, Labor and Welfare, and from the Ministry of Education, Culture, Sports, Science and Technology, and it was confirmed that GM-CSF inhalation was indeed effective. This treatment then spread around the world. Based on the results of the investigator-initiated PAGE study conducted from 2016 to 2017, Nobel Pharma submitted an application for regulatory approval to the Pharmaceuticals and Medical Devices Agency in June 2023, received the approval in March 2024, and launched the product in July 2024.

Particles containing GM-CSF inhaled using a jet or mesh nebulizer are approximately 3 to 5 microns in diameter. However, most of them are trapped in the mouth, pharynx, larynx, trachea, and relatively large bronchi, and only a small amount reach the alveoli. However, measuring GM-CSF in the blood after inhalation administration to monkeys and humans revealed that the concentration in the blood reaches its peak 1 to 2 hours after inhalation. When a patient inhales GM-CSF and it reaches the alveoli, anti-GM-CSF autoantibodies are already in position there, and most of the GM-CSF is likely to be neutralized. However, if even a small amount of unneutralized GM-CSF remains, it can revitalize weakened alveolar macrophages. When the anti-GM-CSF neutralizing autoantibodies that move into the patient's alveoli overpower the GM-CSF produced by the patient's alveoli, GM-CSF cannot bind to the alveolar macrophages remaining in the alveoli; thus, the disease appears to progress. However, additional inhaled GM-CSF may overcome the neutralizing ability of anti-GM-CSF autoantibodies and bind to alveolar macrophages to restore their function.