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Functional, Biophysical, and Structural Characterization of Human IgG1 and IgG4 Fc Variants with Ablated Immune Functionality

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Antibodies 2017, 6(3), 12; https://doi.org/10.3390/antib6030012
Received: 19 July 2017 / Revised: 20 August 2017 / Accepted: 21 August 2017 / Published: 1 September 2017
(This article belongs to the Special Issue Monoclonal Antibodies)
Engineering of fragment crystallizable (Fc) domains of therapeutic immunoglobulin (IgG) antibodies to eliminate their immune effector functions while retaining other Fc characteristics has numerous applications, including blocking antigens on Fc gamma (Fcγ) receptor-expressing immune cells. We previously reported on a human IgG2 variant termed IgG2σ with barely detectable activity in antibody-dependent cellular cytotoxicity, phagocytosis, complement activity, and Fcγ receptor binding assays. Here, we extend that work to IgG1 and IgG4 antibodies, alternative subtypes which may offer advantages over IgG2 antibodies. In several in vitro and in vivo assays, the IgG1σ and IgG4σ variants showed equal or even lower Fc-related activities than the corresponding IgG2σ variant. In particular, IgG1σ and IgG4σ variants demonstrate complete lack of effector function as measured by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and in vivo T-cell activation. The IgG1σ and IgG4σ variants showed acceptable solubility and stability, and typical human IgG1 pharmacokinetic profiles in human FcRn-transgenic mice and cynomolgus monkeys. In silico T-cell epitope analyses predict a lack of immunogenicity in humans. Finally, crystal structures and simulations of the IgG1σ and IgG4σ Fc domains can explain the lack of Fc-mediated immune functions. These variants show promise for use in those therapeutic antibodies and Fc fusions for which the Fc domain should be immunologically “silent”. View Full-Text
Keywords: Fc engineering; silent effector function; IgG1; IgG2; IgG4; IgG sigma; developability; pharmacokinetics; crystal structure Fc engineering; silent effector function; IgG1; IgG2; IgG4; IgG sigma; developability; pharmacokinetics; crystal structure
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MDPI and ACS Style

Tam, S.H.; McCarthy, S.G.; Armstrong, A.A.; Somani, S.; Wu, S.-J.; Liu, X.; Gervais, A.; Ernst, R.; Saro, D.; Decker, R.; Luo, J.; Gilliland, G.L.; Chiu, M.L.; Scallon, B.J. Functional, Biophysical, and Structural Characterization of Human IgG1 and IgG4 Fc Variants with Ablated Immune Functionality. Antibodies 2017, 6, 12. https://doi.org/10.3390/antib6030012

AMA Style

Tam SH, McCarthy SG, Armstrong AA, Somani S, Wu S-J, Liu X, Gervais A, Ernst R, Saro D, Decker R, Luo J, Gilliland GL, Chiu ML, Scallon BJ. Functional, Biophysical, and Structural Characterization of Human IgG1 and IgG4 Fc Variants with Ablated Immune Functionality. Antibodies. 2017; 6(3):12. https://doi.org/10.3390/antib6030012

Chicago/Turabian Style

Tam, Susan H., Stephen G. McCarthy, Anthony A. Armstrong, Sandeep Somani, Sheng-Jiun Wu, Xuesong Liu, Alexis Gervais, Robin Ernst, Dorina Saro, Rose Decker, Jinquan Luo, Gary L. Gilliland, Mark L. Chiu, and Bernard J. Scallon 2017. "Functional, Biophysical, and Structural Characterization of Human IgG1 and IgG4 Fc Variants with Ablated Immune Functionality" Antibodies 6, no. 3: 12. https://doi.org/10.3390/antib6030012

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