Optimizing therapeutic antibody function: progress with Fc domain engineering

BioDrugs. 2011 Feb 1;25(1):1-11. doi: 10.2165/11537830-000000000-00000.


Since the establishment of monoclonal antibody production using hybridoma technology in the mid-1970s, there has been expanding progress and continuous technological improvement in the development of therapeutic antibodies. The initial technological breakthroughs involved reduction of immunogenicity and thus enabled repeated administration. The establishment of chimeric, humanized, and fully human antibodies has led to the great success of several ‘second-generation’ therapeutic antibodies, such as rituximab, trastuzumab, cetuximab, and bevacizumab. However, there still exists an urgent demand for improvement in the efficacy of the current antibody therapeutics, which is not yet fully satisfactory for patients. Based on the current understanding of the clinical mechanisms of several therapeutic antibodies, many now believe that Fc-mediated functions (e.g. antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and neonatal Fc receptor [FcRn]-mediated storage) will improve the clinical outcomes of therapeutic antibodies. The present review focuses on the recent progress in the development of ‘Fc engineering,’ which dramatically improves (and sometimes silences) Fc-mediated functions. These achievements can be classified into two technological approaches: (i) introducing amino acid mutations and (ii) modifying Fc-linked oligosaccharide structures. The effectiveness of multiple third-generation therapeutic antibodies armed with various engineered Fcs is now ready to be tested in clinical trials.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / genetics*
  • Antibodies, Monoclonal / physiology
  • Antibodies, Monoclonal / therapeutic use*
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / physiology
  • Histocompatibility Antigens Class I / therapeutic use
  • Humans
  • Immunoglobulin Fc Fragments / genetics*
  • Immunoglobulin Fc Fragments / therapeutic use
  • Mutation / genetics
  • Protein Engineering / standards
  • Protein Engineering / trends*
  • Protein Structure, Secondary / genetics
  • Receptors, Fc / genetics*
  • Receptors, Fc / physiology
  • Receptors, Fc / therapeutic use


  • Antibodies, Monoclonal
  • Histocompatibility Antigens Class I
  • Immunoglobulin Fc Fragments
  • Receptors, Fc
  • Fc receptor, neonatal