5HVW: Monomeric Igg4 Fc

Citation:
Abstract
The immunoglobulin Fc region is a homodimer consisted of two sets of CH2 and CH3 domains and has been exploited to generate two-arm protein fusions with high expression yields, simplified purification processes and extended serum half-life. However, attempts to generate one-arm fusion proteins with monomeric Fc, with one set of CH2 and CH3 domains, are often plagued with challenges such as weakened binding to FcRn or partial monomer formation. Here, we demonstrate the generation of a stable IgG4 Fc monomer with a unique combination of mutations at the CH3-CH3 interface using rational design combined with in vitro evolution methodologies. In addition to size-exclusion chromatography and analytical ultracentrifugation, we used multi-angle light scattering (MALS) to show that the engineered Fc monomer exhibits excellent monodispersity. Furthermore, crystal structure analysis (PDB ID: 5HVW) reveals monomeric properties supported by disrupted interactions at the CH3-CH3 interface. Monomeric Fc fusions with Fab or scFv achieved FcRn binding and serum half-life comparable to wildtype IgG. These results demonstrate that this monomeric IgG4 Fc is a promising therapeutic platform to extend the serum half-life of proteins in a monovalent format.
PDB ID: 5HVWDownload
MMDB ID: 142435
PDB Deposition Date: 2016/1/28
Updated in MMDB: 2016/08
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
Similar Structures:
Biological Unit for 5HVW: monomeric; determined by author
Molecular Components in 5HVW
Label Count Molecule
Protein (1 molecule)
1
IG Gamma-4 Chain C Region(Gene symbol: IGHG4)
Molecule annotation
Chemicals (12 molecules)
1
4
2
1
3
2
4
1
5
1
6
2
7
1
* Click molecule labels to explore molecular sequence information.

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