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Link to original content: https://pubmed.ncbi.nlm.nih.gov/29375551/
Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics - PubMed Skip to main page content
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Review
. 2018 Jan 8:8:1860.
doi: 10.3389/fimmu.2017.01860. eCollection 2017.

Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics

Chunpeng Yang  1   2 , Xinyu Gao  1   2 , Rui Gong  1
Affiliations
Review

Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics

Chunpeng Yang et al. Front Immunol. .

Abstract

Therapeutic monoclonal antibodies and Fc-fusion proteins are successfully used in treatment of various diseases mainly including cancer, immune disease, and viral infection, which belong to the Fc-based therapeutics. In recent years, engineered Fc-derived antibody domains have also shown potential for Fc-based therapeutics. To increase the druggability of Fc-based therapeutic candidates, many efforts have been made in optimizing physicochemical properties and functions mediated by Fc fragment. The desired result is that we can simultaneously obtain Fc variants with increased physicochemical properties in vitro and capacity of mediating appropriate functions in vivo. However, changes of physicochemical properties of Fc may result in alternation of Fc-mediated functions and vice versa, which leads to undesired outcomes for further development of Fc-based therapeutics. Therefore, whether modified Fc fragments are suitable for achievement of expected clinical results or not needs to be seriously considered. Now, this question comes to be noticed and should be figured out to make better translation from the results of laboratory into clinical applications. In this review, we summarize different strategies on engineering physicochemical properties of Fc, and preliminarily elucidate the relationships between modified Fc in vitro and the subsequent therapeutic influence in vivo.

Keywords: Fc-based therapeutics; Fc-fusion protein; aggregation; monoclonal antibody; optimization; physicochemical property; stability.

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Figures

Figure 1
Figure 1
Structure of Fc [PDB 3AVE (47)] presented by PyMOL. The CH2 and CH3 domains are colored by blue and green, respectively; the residues (N297, S298, and T299) in glycosylation motif in CH2 are colored dark red; the residues (T366, L368, P395, F405, Y407, and K409) involved in the interactions between two CH3 domains are colored by light red; and the oligosaccharides and native disulfides are colored by lemon and yellow, respectively.
Figure 2
Figure 2
The structures of CH2 and CH3 domains [PDB 3AVE (47)] with different mutations for introduction of additional disulfide bonds presented by PyMOL. (A) CH2 mutant L242C/K334C. (B) CH2 mutant V240C/K334C. (C) CH2 mutant A287C/L306C. (D) CH2 mutant R292C/V302C. (E) CH3 mutant S375C/P396C. (F) CH3 mutant P343C/A431C. (G) CH3 mutant P343C/A431C/K447C. The native disulfide bond is colored by yellow, whereas the mutated residues for additional disulfide bonds are colored by red. All the marked distance is the measured between two α-carbon atoms in related two cysteines after mutagenesis by using PyMOL.
Figure 3
Figure 3
The structures of CH2 and CH3 domains [PDB 3AVE (47)] with optimized non-covalent interactions presented by PyMOL. (A) CH2 L235K/L309K mutant. (B) CH2 L234F/L235Q/K322Q/M252Y/S254T/T256E mutant (FQQ–YTE). (C) The residues K392, G402, and L441 in human IgG1 CH3 domain, which can be used to replace the corresponding residues in the bovine CH3 domain (G197, S207, and T246) for increase of the stability. The mutated residues for additional disulfide bonds are colored by red.
Figure 4
Figure 4
Engineered of loop and other regions in CH2 presented by PyMOL. (A) Introduction of an enhanced aromatic sequon (EAS) (Q295F/Y296A) in CH2 loop DE [PDB 3AVE (47)]. The mutated residues are colored by red, whereas the oligosaccharides are colored by lemon color. (B) Truncation of N-terminus of CH2. Seven unstructured residues from A244 to G250 are colored by red, which could be removed [PDB 1HZH (51)].
Figure 5
Figure 5
Structures of three categories of N-linked oligosaccharides in IgG1 CH2. Subscripts indicate the absence (0) or presence (1 and X) of corresponding monosaccharide. X represents a number that is equal or greater than 1 of this monosaccharide. Abbreviations: Gal, galactose; GlcNAc, N-acetylglucosamine; Man, mannose; Fuc, fucose; Sia, sialic acid.
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