Optimal combination of beneficial mutations for improved ADCC effector function of aglycosylated antibodies

Hyun Woung Yoon, Migyeong Jo, Sanghwan Ko, Hyeong Sun Kwon, Chung Su Lim, Byoung Joon Ko, Ji Chul Lee, Sang Taek Jung

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1 Citation (Scopus)

Abstract

The Fc region of IgG antibodies is crucial for binding to Fc receptors expressed on the surfaces of various immune leukocytes and eliciting therapeutic effector functions such as clearance of antibody-opsonized tumor cells. Despite abrogated Fc gamma receptor (FcγR) binding and therapeutic effector function in the absence of N-linked glycosylation at Asn297, the aglycosylated Fc region of IgG antibodies has bioprocessing advantages such as the absence of glycan heterogeneity and simple bacterial antibody production. Therefore, these antibodies have been comprehensively engineered as effector functional units for human therapy. In this work, we constructed a huge library of Fc variants with combinations of 25 beneficial mutations that were previously identified to improve binding of glycosylated or aglycosylated Fc regions to human FcγRs in previous studies. High-throughput screening of the resulting library led to the identification of an aglycosylated Fc variant that exhibited almost double the antibody-dependent cell-mediated cytotoxicity than wild-type glycosylated Fc. All mutations in this aglycosylated Fc variant were derived from previously identified beneficial mutations for engineered aglycosylated Fc variants as opposed to glycosylated variants, suggesting that significantly different sets of beneficial mutations are necessary to improve the effector function of aglycosylated Fc.

Original languageEnglish
Pages (from-to)62-71
Number of pages10
JournalMolecular Immunology
Volume114
DOIs
Publication statusPublished - 2019 Oct

Keywords

  • Aglycosylated IgG
  • Antibody-dependent cell-mediated cytotoxicity
  • Effector functions
  • Fc engineering
  • FcγRIIIa

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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  • Cite this

    Yoon, H. W., Jo, M., Ko, S., Kwon, H. S., Lim, C. S., Ko, B. J., Lee, J. C., & Jung, S. T. (2019). Optimal combination of beneficial mutations for improved ADCC effector function of aglycosylated antibodies. Molecular Immunology, 114, 62-71. https://doi.org/10.1016/j.molimm.2019.07.007