Genomes and Genes
immunoglobulin fc fragments
Summary: Crystallizable fragments composed of the carboxy-terminal halves of both IMMUNOGLOBULIN HEAVY CHAINS linked to each other by disulfide bonds. Fc fragments contain the carboxy-terminal parts of the heavy chain constant regions that are responsible for the effector functions of an immunoglobulin (COMPLEMENT fixation, binding to the cell membrane via FC RECEPTORS, and placental transport). This fragment can be obtained by digestion of immunoglobulins with the proteolytic enzyme PAPAIN.
- Umpierrez G, Blevins T, Rosenstock J, Cheng C, Anderson J, Bastyr E. The effects of LY2189265, a long-acting glucagon-like peptide-1 analogue, in a randomized, placebo-controlled, double-blind study of overweight/obese patients with type 2 diabetes: the EGO study. Diabetes Obes Metab. 2011;13:418-25 pubmed publisher..LY2189265, given to overweight/obese patients with type 2 diabetes for 16 weeks in combination with OAMs, was relatively well tolerated and significantly reduced A1c, blood glucose and body weight. ..
- Wozniak Knopp G, Stadlmann J, Ruker F. Stabilisation of the Fc fragment of human IgG1 by engineered intradomain disulfide bonds. PLoS ONE. 2012;7:e30083 pubmed publisher..5°C for CysP4, 15.5°C for CysP2 and 19°C for the CysP2 and CysP4 disulfide bonds combined in one molecule...
- Lu L, Palaniyandi S, Zeng R, Bai Y, Liu X, Wang Y, et al. A neonatal Fc receptor-targeted mucosal vaccine strategy effectively induces HIV-1 antigen-specific immunity to genital infection. J Virol. 2011;85:10542-53 pubmed publisher..Our data suggest that targeting of FcRn with chimeric immunogens may be an important strategy for mucosal immunization and should be considered a new approach for preventive HIV vaccines. ..
- Barb A, Meng L, Gao Z, Johnson R, Moremen K, Prestegard J. NMR characterization of immunoglobulin G Fc glycan motion on enzymatic sialylation. Biochemistry. 2012;51:4618-26 pubmed..The results suggest new modes by which disialylated Fc can act as an anti-inflammatory effector. ..
- Alessandri L, Ouellette D, Acquah A, Rieser M, LeBlond D, Saltarelli M, et al. Increased serum clearance of oligomannose species present on a human IgG1 molecule. MAbs. 2012;4:509-20 pubmed publisher..These observations were only possible through the application of rigorous analytical methods that we believe will need to be employed when comparing innovator and biosimilar molecules. ..
- Wines B, Trist H, Farrugia W, Ngo C, Trowsdale J, Areschoug T, et al. A conserved host and pathogen recognition site on immunoglobulins: structural and functional aspects. Adv Exp Med Biol. 2012;946:87-112 pubmed publisher..We also propose that some pathogen proteins may promote virulence by affecting the bridging between innate and adaptive immunity. ..
- Wilson N, Yang B, Yang A, Loeser S, Marsters S, Lawrence D, et al. An Fc? receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell. 2011;19:101-13 pubmed publisher..A CD40-agonistic antibody required similar Fc?R interactions to stimulate nuclear factor-?B activity in B cells. Thus, Fc?Rs can drive antibody-mediated receptor signaling in target cells. ..
- Ball C, Fox B, Hufton S, Sharp G, Poole S, Stebbings R, et al. Antibody C region influences TGN1412-like functional activity in vitro. J Immunol. 2012;189:5831-40 pubmed publisher..We propose that the Fc, potentially through restricting flexibility, maintains a favorable V region conformation to allow superagonistic activity. These findings have important implications for Ab design strategies. ..
- Schwab I, Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system?. Nat Rev Immunol. 2013;13:176-89 pubmed publisher..In this Review, we cover the recent insights into the molecular and cellular pathways that are involved in IVIG-mediated immunosuppression, with a particular focus on IVIG as a therapy for IgG-dependent autoimmune diseases. ..
- Zou G, Ochiai H, Huang W, Yang Q, Li C, Wang L. Chemoenzymatic synthesis and Fc? receptor binding of homogeneous glycoforms of antibody Fc domain. Presence of a bisecting sugar moiety enhances the affinity of Fc to Fc?IIIa receptor. J Am Chem Soc. 2011;133:18975-91 pubmed publisher..The synthetic homogeneous Fc glycoforms thus provide a useful tool for elucidating how a fine Fc N-glycan structure precisely affects the function of the Fc domain. ..
- Mizushima T, Yagi H, Takemoto E, Shibata Koyama M, Isoda Y, Iida S, et al. Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans. Genes Cells. 2011;16:1071-80 pubmed publisher..Our results offer a structural basis for improvement in ADCC of therapeutic antibodies by defucosylation. ..
- Ungerer M, Rosport K, Bültmann A, Piechatzek R, Uhland K, Schlieper P, et al. Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation. 2011;123:1891-9 pubmed publisher..URL: www.clinicaltrials.gov. Unique identifier: NCT 01042964. URL: eudract.ema.europa.eu. Identifier: 2005-004656-12. ..
- Goetze A, Liu Y, Zhang Z, Shah B, Lee E, Bondarenko P, et al. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology. 2011;21:949-59 pubmed publisher..High-mannose content of therapeutic Mabs should be considered an important product quality attribute which may affect pharmacokinetic properties of therapeutic antibodies. ..
- Chu S, Horton H, Pong E, Leung I, Chen H, Nguyen D, et al. Reduction of total IgE by targeted coengagement of IgE B-cell receptor and Fc?RIIb with Fc-engineered antibody. J Allergy Clin Immunol. 2012;129:1102-15 pubmed publisher..XmAb7195 acts by IgE sequestration coupled with an Fc?RIIb-mediated inhibitory mechanism to suppress the formation of IgE-secreting plasma cells and reduce both free and total IgE levels. ..
- Kainer M, Antes B, Wiederkum S, Wozniak Knopp G, Bauer A, Ruker F, et al. Correlation between CD16a binding and immuno effector functionality of an antigen specific immunoglobulin Fc fragment (Fcab). Arch Biochem Biophys. 2012;526:154-8 pubmed publisherAntigen binding immunoglobulin Fc fragments (Fcab) are generated by engineering loop regions in the CH3 domain of human IgG1 Fc...
- Bowden T, Baruah K, Coles C, Harvey D, Yu X, Song B, et al. Chemical and structural analysis of an antibody folding intermediate trapped during glycan biosynthesis. J Am Chem Soc. 2012;134:17554-63 pubmed publisher..Our crystal structure of this intermediate reveals a molecular basis for antibody biogenesis and provides a template for the structure-guided engineering of the protein-glycan interface of therapeutic antibodies. ..
- Li F, Ravetch J. Inhibitory Fc? receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science. 2011;333:1030-4 pubmed publisher..This unexpected requirement for Fc?RIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics. ..
- Cemerski S, Chu S, Moore G, Muchhal U, Desjarlais J, Szymkowski D. Suppression of mast cell degranulation through a dual-targeting tandem IgE-IgG Fc domain biologic engineered to bind with high affinity to Fc?RIIb. Immunol Lett. 2012;143:34-43 pubmed publisher..We propose that in the context of a fully human tandem Fc biologic, high-affinity coengagement of Fc?RI and Fc?RIIb has potential as a novel therapy for allergy and other mast cell and basophil-mediated pathologies. ..
- Wozniak Knopp G, Ruker F. A C-terminal interdomain disulfide bond significantly stabilizes the Fc fragment of IgG. Arch Biochem Biophys. 2012;526:181-7 pubmed publisher..Using them in combination, the Tm of the CH(3) domain was raised by 18 °C and thus restored to the Tm of the wild-type CH(3) domain. Importantly, antigen binding of the modified Fc was not affected by the engineered disulfide bonds. ..
- Traxlmayr M, Lobner E, Antes B, Kainer M, Wiederkum S, Hasenhindl C, et al. Directed evolution of Her2/neu-binding IgG1-Fc for improved stability and resistance to aggregation by using yeast surface display. Protein Eng Des Sel. 2013;26:255-65 pubmed publisher..To sum up, this study presents a very potent and generally applicable method for improving the fold and stability of antibodies, antibody fragments and alternative binding scaffolds. ..
- Müller R, Gräwert M, Kern T, Madl T, Peschek J, Sattler M, et al. High-resolution structures of the IgM Fc domains reveal principles of its hexamer formation. Proc Natl Acad Sci U S A. 2013;110:10183-8 pubmed publisher..Based on small angle X-ray scattering data, we present a model of the ring-shaped Cµ4 structure, which reveals the principles of IgM oligomerization. ..
- Ferrara C, Grau S, Jäger C, Sondermann P, Brünker P, Waldhauer I, et al. Unique carbohydrate-carbohydrate interactions are required for high affinity binding between FcgammaRIII and antibodies lacking core fucose. Proc Natl Acad Sci U S A. 2011;108:12669-74 pubmed publisher..These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions. ..
- Shaughnessy J, Ram S, Bhattacharjee A, Pedrosa J, Tran C, Horvath G, et al. Molecular characterization of the interaction between sialylated Neisseria gonorrhoeae and factor H. J Biol Chem. 2011;286:22235-42 pubmed publisher..These findings provide further insights into the species specificity of gonococcal infections and proof-of-concept of a novel therapeutic approach against gonorrhea, a disease rapidly becoming resistant to conventional antibiotics...
- Nagashima H, Kaneko K, Yamanoi A, Motoi S, Konakahara S, Kohroki J, et al. TNF receptor II fusion protein with tandemly repeated Fc domains. J Biochem. 2011;149:337-46 pubmed publisher..This may be the case not only for TNFRII-Fc but also for other receptor-Fc fusion proteins. ..
- Barb A, Prestegard J. NMR analysis demonstrates immunoglobulin G N-glycans are accessible and dynamic. Nat Chem Biol. 2011;7:147-53 pubmed publisher..These findings suggest a role for Fc-glycan dynamics in Fc-receptor interactions and enzymatic glycan remodeling. ..
- Traxlmayr M, Faissner M, Stadlmayr G, Hasenhindl C, Antes B, Ruker F, et al. Directed evolution of stabilized IgG1-Fc scaffolds by application of strong heat shock to libraries displayed on yeast. Biochim Biophys Acta. 2012;1824:542-9 pubmed publisher..These data clearly demonstrate the importance and efficacy of the presented strategy for selection of stabilizing mutations in proteins of high intrinsic stability within reasonable time. ..
- Grunberger G, Chang A, Garcia Soria G, Botros F, Bsharat R, Milicevic Z. Monotherapy with the once-weekly GLP-1 analogue dulaglutide for 12 weeks in patients with Type 2 diabetes: dose-dependent effects on glycaemic control in a randomized, double-blind, placebo-controlled study. Diabet Med. 2012;29:1260-7 pubmed publisher..The most common adverse events were nausea and diarrhoea. The observed dulaglutide dose-dependent reduction in HbA(1c) and its acceptable safety profile support further clinical development for treatment of Type 2 diabetes. ..
- Yu M, Brown D, Reed C, CHUNG S, Lutman J, Stefanich E, et al. Production, characterization, and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans. MAbs. 2012;4:475-87 pubmed publisher..In addition, we identified the presence of a mannosidase in mouse serum that converted most Man8/9 to Man6 after 24 h. ..
- Beck A, Wagner Rousset E, Bussat M, Lokteff M, Klinguer Hamour C, Haeuw J, et al. Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol. 2008;9:482-501 pubmed
- Chu S, Vostiar I, Karki S, Moore G, Lazar G, Pong E, et al. Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies. Mol Immunol. 2008;45:3926-33 pubmed publisher..The use of a single antibody to suppress B cell functions by coengagement of BCR and FcgammaRIIb may represent a novel approach in the treatment of B cell-mediated autoimmune diseases. ..
- Wozniak Knopp G, Bartl S, Bauer A, Mostageer M, Woisetschlager M, Antes B, et al. Introducing antigen-binding sites in structural loops of immunoglobulin constant domains: Fc fragments with engineered HER2/neu-binding sites and antibody properties. Protein Eng Des Sel. 2010;23:289-97 pubmed publisher..Our data demonstrate that the Fcab scaffold combines all features of normal antibodies in a small 50 kD homodimeric protein: antigen binding, effector functions and long half-life in vivo. ..
- Taylor A, Sutton B, Calvert R. Mutations in an avian IgY-Fc fragment reveal the locations of monocyte Fc receptor binding sites. Dev Comp Immunol. 2010;34:97-101 pubmed publisher..This finding, together with the phylogenetic relationship of the antibodies and their receptors, indicates that a substantial shift in the nature of Fc receptor binding occurred during the evolution of mammalian IgG and IgE. ..
- Girardi E, Holdom M, Davies A, Sutton B, Beavil A. The crystal structure of rabbit IgG-Fc. Biochem J. 2009;417:77-83 pubmed publisher..Rabbit IgG, through this high-resolution structure of its Fc region, thus continues to offer new insights into antibody structure. ..
- An Z, Forrest G, Moore R, Cukan M, Haytko P, Huang L, et al. IgG2m4, an engineered antibody isotype with reduced Fc function. MAbs. 2009;1:572-9 pubmed..An IgG2m4 antibody has an overall reduction in complement and Fc gamma receptor binding in in vitro binding analyses while maintaining the normal in vivo serum half-life in rhesus. ..
- Qi Z, Pan C, Lu H, Shui Y, Li L, Li X, et al. A recombinant mimetics of the HIV-1 gp41 prehairpin fusion intermediate fused with human IgG Fc fragment elicits neutralizing antibody response in the vaccinated mice. Biochem Biophys Res Commun. 2010;398:506-12 pubmed publisher..These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines. ..
- Liu X, Pop L, Vitetta E. Engineering therapeutic monoclonal antibodies. Immunol Rev. 2008;222:9-27 pubmed publisher..In this review we discuss these redesigned mAbs and current data concerning their evaluation both in vitro and in vivo. ..
- Shukla A, Gupta P, Han X. Protein aggregation kinetics during Protein A chromatography. Case study for an Fc fusion protein. J Chromatogr A. 2007;1171:22-8 pubmed..The results presented here are anticipated to assist the development of Protein A process conditions for products that are prone to form high molecular weight aggregates during column elution. ..
- Seth P, Wang Z, Pister A, Zafar M, Kim S, Guise T, et al. Development of oncolytic adenovirus armed with a fusion of soluble transforming growth factor-beta receptor II and human immunoglobulin Fc for breast cancer therapy. Hum Gene Ther. 2006;17:1152-60 pubmed..On the basis of these results we believe that it may be feasible to develop a cancer gene therapy approach using Ad.sTbetaRFc as an antitumor agent. ..
- Kanda Y, Yamada T, Mori K, Okazaki A, Inoue M, Kitajima Miyama K, et al. Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology. 2007;17:104-18 pubmed..The present study provides basic information on the effects of core fucose-lacking N-linked Fc oligosaccharides on antibody biological activities. ..
- Ghumra A, Semblat J, McIntosh R, Raza A, Rasmussen I, Braathen R, et al. Identification of residues in the Cmu4 domain of polymeric IgM essential for interaction with Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). J Immunol. 2008;181:1988-2000 pubmed..We have therefore shown that PfEMP1 is an Fc-binding protein of malaria parasites specific for polymeric human IgM, and that it shows functional similarities with Fc-binding proteins from pathogenic bacteria. ..
- Nasser R, Pelegrin M, Michaud H, Plays M, Piechaczyk M, Gros L. Long-lasting protective antiviral immunity induced by passive immunotherapies requires both neutralizing and effector functions of the administered monoclonal antibody. J Virol. 2010;84:10169-81 pubmed publisher..Such complementary effects of administered MAbs must be taken into consideration for the improvement of future antiviral MAb-based immunotherapies. ..
- Ren F, Li B, Zhang N, Cao M, Dan W, Zhang S. Expression, purification and characterization of anti-BAFF antibody secreted from the yeast Pichia pastoris. Biotechnol Lett. 2008;30:1075-80 pubmed publisher..The scFv-Fc antibody was purified and 56 mg was obtained from 1 l of culture supernatant. It retained high binding activity to both soluble BAFF and membrane-bound BAFF. ..
- Saxon A, Kepley C, Zhang K. "Accentuate the negative, eliminate the positive": engineering allergy therapeutics to block allergic reactivity through negative signaling. J Allergy Clin Immunol. 2008;121:320-5 pubmed..Fcgamma-Fel d 1 blocked human mast cell Fel d 1-induced allergic reactivity in vitro and in vivo in murine models while functioning as an immunogen but not as an allergen. ..
- Chen H, Xu X, Jones I. Immunogenicity of the outer domain of a HIV-1 clade C gp120. Retrovirology. 2007;4:33 pubmed..Immunogenicity is substantial when targeted to antigen presenting cells but shows V3 dominance in the polyvalent response. The gp120 outer domain has potential as a candidate vaccine component. ..
- Rispens T, Ooievaar De Heer P, Vermeulen E, Schuurman J, van der Neut Kolfschoten M, Aalberse R. Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc-Fc interactions. J Immunol. 2009;182:4275-81 pubmed publisher..By contrast, IgG4 Fc recognizes IgG1 only after a conformational change that renders CH3(IgG1) accessible to an interaction with the CH3(IgG4). Such Fc interactions may enhance Ag binding of IgG4 in vivo. ..