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Engineered antibody CH2 domains binding to nucleolin: Isolation, characterization and improvement of aggregation
Li, Dezhi1; Gong, Rui3; Zheng, Jun2; Chen, Xihai4; Dimitrov, Dimiter S.5; Zhao, Qi2

Smaller recombinant antibody fragments are now emerging as alternatives of conventional antibodies. Especially, immunoglobulin (Ig) constant CH2 domain and engineered CH2 with improved stability are promising as scaffolds for selection of specific binders to various antigens. We constructed a yeast display library based on an engineered human IgG1 CH2 scaffold with diversified loop regions. A group of CH2 binders were isolated from this yeast display library by panning against nucleolin, which is a tumor associated antigen involved in cell proliferation, tumor cell growth and angiogenesis. Out of 20 mutants, we selected 3 clones exhibiting relatively high affinities to nucleolin on yeasts. However, recombinant CH2 mutants aggregated when they were expressed. To find the mechanism of the aggregation, we employed computational prediction approaches through structural homology models of CH2 binders. The analysis of potential aggregation prone regions (APRs) and solvent accessible surface areas (ASAs) indicated two hydrophobic residues, Val(264) and Leu(309), in the beta-sheet, in which replacement of both charged residues led to significant decrease of the protein aggregation. The newly identified CH2 binders could be improved to use as candidate therapeutics or research reagents in the future.

KeywordAntibody Domain Ch2 Nucleolin Yeast Display Monoclonal Antibody Aggregation Prone Region
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Indexed BySCIE
WOS Research AreaBiochemistry & Molecular Biology ; Biophysics
WOS SubjectBiochemistry & Molecular Biology ; Biophysics
WOS IDWOS:000396798300037
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Cited Times [WOS]:14   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.Xiamen Univ, Coll Life Sci, Xiamen, Fujian, Peoples R China
2.Univ Macau, Fac Hlth Sci, E12-3022, Taipa, Macau, Peoples R China
3.Chinese Acad Sci, Wuhan Inst Virol, CAS Key Lab Special Pathogens & Biosafety, Wuhan, Hunan, Peoples R China
4.Harbin Med Univ, Affiliated Hosp 4, Dept Gen Surg, Harbin 150006, Heilongjiang, Peoples R China
5.Natl Inst Hlth, Prot Interact Sect, Canc Inflammat Program, Ctr Canc Res,Natl Canc Inst, Frederick, MD USA
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Li, Dezhi,Gong, Rui,Zheng, Jun,et al. Engineered antibody CH2 domains binding to nucleolin: Isolation, characterization and improvement of aggregation[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2017,485(2):446-453.
APA Li, Dezhi,Gong, Rui,Zheng, Jun,Chen, Xihai,Dimitrov, Dimiter S.,&Zhao, Qi.(2017).Engineered antibody CH2 domains binding to nucleolin: Isolation, characterization and improvement of aggregation.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,485(2),446-453.
MLA Li, Dezhi,et al."Engineered antibody CH2 domains binding to nucleolin: Isolation, characterization and improvement of aggregation".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 485.2(2017):446-453.
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