Fc-engineered antibodies with immune effector functions completely abolished

PLoS One. 2021 Dec 21;16(12):e0260954. doi: 10.1371/journal.pone.0260954. eCollection 2021.

Abstract

Elimination of the binding of immunoglobulin Fc to Fc gamma receptors (FcγR) is highly desirable for the avoidance of unwanted inflammatory responses to therapeutic antibodies and fusion proteins. Many different approaches have been described in the literature but none of them completely eliminates binding to all of the Fcγ receptors. Here we describe a set of novel variants having specific amino acid substitutions in the Fc region at L234 and L235 combined with the substitution G236R. They show no detectable binding to Fcγ receptors or to C1q, are inactive in functional cell-based assays and do not elicit inflammatory cytokine responses. Meanwhile, binding to FcRn, manufacturability, stability and potential for immunogenicity are unaffected. These variants have the potential to improve the safety and efficacy of therapeutic antibodies and Fc fusion proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Antibody Affinity
  • Antibody-Dependent Cell Cytotoxicity*
  • Complement C1q / genetics
  • Complement C1q / immunology
  • Complement C1q / metabolism*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Immunoglobulin Fc Fragments / genetics
  • Immunoglobulin Fc Fragments / immunology
  • Immunoglobulin Fc Fragments / metabolism*
  • Immunoglobulin G / genetics
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism*
  • Protein Binding
  • Protein Engineering
  • Receptors, Fc / genetics
  • Receptors, Fc / immunology
  • Receptors, Fc / metabolism*
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology
  • Receptors, IgG / metabolism*

Substances

  • Histocompatibility Antigens Class I
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Receptors, Fc
  • Receptors, IgG
  • Complement C1q
  • Fc receptor, neonatal

Grants and funding

This study was primarily funded by mAbsolve Limited https://mabsolve.com/. Some of the Biacore experiments were funded by Antibody Analytics Ltd https://www.antibodyanalytics.com/. IW was and SA is and employee of Absolute Antibody Ltd, JF is an employee of ProImmune Limited, LAJ is an employee of Antibody Analytics Limited, DN is an employee of Reading Scientific Services Limited, OQ is an employee of Celentyx Limited, GW is an employee of Abzena Limited and IW and GH are employees of mAbsolve Limited. mAbsolve Limited played an indirect role in the study design, data collection and analysis, decision to publish and preparation of the manuscript to the extent that IW and GH are founding shareholders and directors of mAbsolve Limited. Antibody Analytics Ltd provided support in the form of salary for LAJ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section.