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Structural motifs involved in human IgG antibody effector functions

J Greenwood1, M Clark, H Waldmann

  • 1Department of Pathology, University of Cambridge.

European Journal of Immunology
|May 1, 1993
PubMed
Summary

Humanized IgG antibodies targeting CDw52 show varying efficacy. Protein engineering identified the CH2 domain

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Area of Science:

  • Immunology
  • Protein Engineering
  • Therapeutic Antibodies

Background:

  • Humanized IgG antibodies against the CAMPATH-1 antigen (CDw52) exhibit lympholytic properties in vitro and in vivo.
  • Differences in function exist between human IgG1 and IgG4 isotypes of these antibodies.

Purpose of the Study:

  • To identify structural motifs responsible for functional differences between human IgG1 and IgG4 antibodies targeting CDw52.
  • To explore protein engineering strategies for enhancing therapeutic potency.

Main Methods:

  • Creation of heavy chain domain-switch and intra-domain recombinant antibodies.
  • Assessment of antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated lysis.

Main Results:

  • The carboxy-terminal half of the CH2 domain plays a crucial role in differential ADCC and complement lysis.
  • While hIgG4 CAMPATH-1 was sometimes ineffective at ADCC, efficacy varied among individuals, with some showing activity for IgG4 and other IgG subclasses.
  • Human IgG1 remains the preferred isotype for in vivo lytic therapy.

Conclusions:

  • The CH2 domain is critical for effector functions of humanized IgG antibodies against CDw52.
  • Protein engineering of novel antibodies with enhanced hinge-CH2 structures may improve therapeutic outcomes.
  • Human IgG1 is the most effective isotype for in vivo therapeutic applications.

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