Abstract
Human IgG4 (hIgG4) has weak pro-inflammatory activity. The structural basis for this is still unclear. Here a 3D model of myeloma hIgG4 was created at ∼3nm resolution using electron microscopy (EM) with negative staining and single-particle 3D reconstruction. The hIgG4 model reveals relatively rigid asymmetric Y-like structure. The model shows that one Fab subunit is closer to the upper portion of the Fc subunit (CH2 domain) than the other Fab. This is in agreement with X-ray crystallography and X-ray/neutron scattering, recently published by others. The same hIgG4 sample was studied with differential scanning calorimetry (DSC) and fluorescence. The thermodynamics and fluorescence observations indicate that one CH2 domain displays less conformational stability than the other. This finding is consistent with the flipping of one CH2 domain, observed in pembrolizumab (recombinant hIgG4) by X-ray crystallography. The specific feature of hIgG4 CH2 domains together with relatively rigid asymmetric Y-like structure, in which one Fab subunit is closer to the upper portion of the Fc subunit (CH2 domain) than the other Fab, can explain the unique biological properties of hIgG4, such as its weak pro-inflammatory activity.
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