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Related Experiment Videos

In vitro characterization of five humanized OKT3 effector function variant antibodies.

D Xu1, M L Alegre, S S Varga

  • 1Drug Discovery, R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869, USA.

Cellular Immunology
|March 16, 2000
PubMed
Summary
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Modified Orthoclone OKT3 antibodies reduce side effects like human anti-mouse antibody response and cytokine release syndrome. These engineered antibodies maintain potent immunosuppressive effects for renal allograft rejection reversal.

Area of Science:

  • Immunology
  • Transplantation Medicine
  • Biotechnology

Background:

  • Orthoclone OKT3 (mOKT3) effectively reverses steroid-resistant renal allograft rejection.
  • Wider use is limited by human anti-mouse antibody response (HAMA) and cytokine release syndrome (CRS).
  • CRS involves T cell/monocyte activation and complement cascade activation, mediated by antibody Fc regions.

Purpose of the Study:

  • To engineer humanized IgG1 and IgG4-based OKT3 antibodies with Fc mutations.
  • To reduce HAMA and CRS while retaining immunosuppressive efficacy.
  • To investigate the role of specific amino acid residues (234, 235, 318) in Fc binding and complement fixation.

Main Methods:

  • Construction of five huIgG1- and huIgG4-based OKT3 wild-type and Fc mutant antibodies.

Related Experiment Videos

  • Characterization of binding affinity to FcgammaRI and FcgammaRII.
  • Assessment of T cell activation, cytokine release, and complement fixation (C1q binding).

    • Main Results:

    • huOKT3gamma1(A(234), A(235)) and huOKT3gamma4(A(234), A(235)) showed >100-fold reduced binding to FcgammaRI/II.
    • These mutants exhibited significantly reduced T cell activation and cytokine release.
    • huOKT3gamma1(A(234), A(235)) demonstrated complete inactivity in complement fixation and reduced HAMA/CRS in vivo.
    • All engineered antibodies retained potent in vitro immunosuppressive effects.

    Conclusions:

    • Fc mutations at amino acids 234 and 235 significantly reduce HAMA and CRS.
    • Engineered OKT3 variants maintain immunosuppressive efficacy for renal allograft rejection.
    • These modified antibodies represent a safer therapeutic option for transplant patients.