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. 2012 Oct;4(10):1015-28.
doi: 10.1002/emmm.201201379. Epub 2012 Jul 26.

Fc-fusion Proteins: New Developments and Future Perspectives

Free PMC article

Fc-fusion Proteins: New Developments and Future Perspectives

Daniel M Czajkowsky et al. EMBO Mol Med. .
Free PMC article


Since the first description in 1989 of CD4-Fc-fusion antagonists that inhibit human immune deficiency virus entry into T cells, Fc-fusion proteins have been intensely investigated for their effectiveness to curb a range of pathologies, with several notable recent successes coming to market. These promising outcomes have stimulated the development of novel approaches to improve their efficacy and safety, while also broadening their clinical remit to other uses such as vaccines and intravenous immunoglobulin therapy. This increased attention has also led to non-clinical applications of Fc-fusions, such as affinity reagents in microarray devices. Here we discuss recent results and more generally applicable strategies to improve Fc-fusion proteins for each application, with particular attention to the newer, less charted areas.


Figure 1
Figure 1. The structure of a prototypic IgG Fc-fusion and the means by which it can be presently modified

Fc-fusions are homodimers in which an Fc domain of an antibody is covalently linked to another protein. The fusion partner is usually directly attached to the flexible hinge (as shown), the length and sequence of which varies between different IgG subclasses. Also shown is the approximate position of the N-linked oligosaccharides attached at Asn 297 in the IgG1 Fc-domain.

There are a number of specific changes to the (monomeric) fusion construct that can be made to improve efficacy, as detailed in the text. A summary of these specific changes is included in Supporting Information Table S2.

Fc-fusions can also be polymerized through engineered disulphide bridges localized to the CH2–CH3 junction and 18 amino-acid carboxy-terminal extensions known as tailpieces. The panel on the right shows atomic force microscopy images of hexameric hIgM-Fc fusions (attached to a malarial antigen) showing six-fold symmetric star-shaped complexes. The smaller radial projections are most likely the antigens (reproduced with permission; Mekhaiel et al, 2011b). Each panel is 75 × 75 nm2.

Figure 2
Figure 2. Different capabilities for different Fc-fusion stoichiometries

Polymeric Fc-fusions are expected to greatly increase the effectiveness of therapeutic fusions that function either by binding free ligands (such as etanercept) or by interacting with carbohydrate-receptors in IVIG (for complexes without the fusion partner), as a consequence of their greater valency. Monomeric versions would be expected to exhibit more rapid tissue penetration than the polymers, although both can likely access similar regions (Kaveri et al, ; Vollmers & Brandlein, 2006).

Monomeric and polymeric Fc-fusions interact with fundamentally different sets of FcRs. The clustering of low-affinity FcRs on APCs by polymeric Fc-fusions would initiate signals required by APCs for their maturation and development, essential steps in effective vaccination.

Monomeric Fc-fusions can be coupled to protein G/A coated micron-sized beads to high, though variable, stoichiometry for the detection of critical low-affinity protein:protein or protein:drug interactions in protein microarrays. By comparison, polymeric Fc-fusions as nanosized Fc-scaffolds might be more suitable to sensitive in vivo assays where heavy beads are inappropriate.

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