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Updated: May 20, 2026
A Cell Free Assay System Estimating the Neutralizing Capacity of GM-CSF Antibody using Recombinant Soluble GM-CSF Receptor
Published on: June 27, 2011
Molecular structure of human GM-CSF in complex with a disease-associated anti-human GM-CSF autoantibody and its
Michaela Blech1, Daniel Seeliger, Barbara Kistler
1Department of Lead Identification and Optimization Support, Structural Research Group, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach, Germany. michaela.blech@boehringer-ingelheim.com
Abstract:
Polyclonal autoantibodies against human GM-CSF (granulocyte/macrophage colony-stimulating factor) are a hallmark of PAP (pulmonary alveolar proteinosis) and several other reported autoimmune diseases. MB007 is a high-affinity anti-(human GM-CSF) autoantibody isolated from a patient suffering from PAP which shows only modest neutralization of GM-CSF bioactivity. We describe the first crystal structure of a cytokine-directed human IgG1λ autoantibody-binding fragment (Fab) at 1.9 Å (1 Å=0.1 nm) resolution. Its CDR3-H substantially differs from all VH7 germline IgG1 structures reported previously. We derive a reliable model of the antigen-autoantibody complex by using NMR chemical shift perturbation data in combination with computational methods. Superposition of the modelled complex structure with the human GM-CSF-GM-CSF ternary receptor complex reveals only little overlap between receptor and Fab when bound to GM-CSF. Our model provides a structural basis for understanding the mode of action of the MB007 autoantibody.
Insights
Researchers determined the structure of an autoantibody targeting granulocyte-macrophage colony-stimulating factor (GM-CSF). This autoantibody, MB007, found in pulmonary alveolar proteinosis, shows limited GM-CSF neutralization, offering insights into autoimmune disease mechanisms.
Area of Science:
- Structural biology
- Immunology
- Biochemistry
Background:
- Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) are characteristic of pulmonary alveolar proteinosis (PAP) and other autoimmune conditions.
- MB007 is a high-affinity autoantibody targeting human GM-CSF, isolated from a PAP patient, with modest neutralization capacity.
Purpose of the Study:
- To determine the crystal structure of the MB007 autoantibody-binding fragment (Fab).
- To model the complex between MB007 and human GM-CSF.
- To elucidate the structural basis for the autoantibody's mode of action.
Main Methods:
- X-ray crystallography was used to determine the Fab structure at 1.9 Å resolution.
- Nuclear Magnetic Resonance (NMR) chemical shift perturbation and computational methods were employed to model the antigen-autoantibody complex.
- The modelled complex was superimposed with the human GM-CSF-receptor complex.
Main Results:
- The crystal structure of the human IgG1λ autoantibody Fab fragment (MB007) targeting GM-CSF was determined.
- The CDR3-H region of MB007 significantly differs from previously reported VH7 germline IgG1 structures.
- The modelled complex revealed minimal overlap between the autoantibody and the GM-CSF receptor binding sites.
Conclusions:
- The study provides the first crystal structure of a cytokine-directed human autoantibody Fab fragment.
- The structural model offers insights into how MB007 binds GM-CSF without significantly blocking receptor interaction.
- This work lays the foundation for understanding the structural mechanisms underlying autoimmune diseases involving anti-GM-CSF autoantibodies.
