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Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity

Christian Binder1,2, Felix Sellberg1,2, Filip Cvetkovski2

  • 1Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, Sweden.

Frontiers in Immunology
|March 1, 2021
PubMed

Insights

Siplizumab, an anti-CD2 antibody, activates NK cells via FcγRIIIA binding, leading to T and NK cell depletion. This mechanism shows promise for transplantation therapies with minimal off-target effects.

Area of Science:

  • Immunology
  • Cell Biology
  • Pharmacology

Background:

  • Glycoprotein CD2 is crucial for T and NK cell functions, including cell conjugation and signaling.
  • CD2 plays a key role in natural NK cell cytotoxicity but is less critical in antibody-mediated cytotoxicity.
  • Siplizumab is an anti-CD2 monoclonal antibody being investigated for transplantation.

Purpose of the Study:

  • To investigate the effects of CD2 and Fc gamma receptor binding by siplizumab and Fc-silent anti-CD2 antibodies.
  • To assess NK cell fratricide, natural cytotoxicity, and antibody-dependent cytotoxicity.
  • To evaluate siplizumab's potential as a biopharmaceutical for T and NK cell depletion.

Main Methods:

  • Utilized allogeneic mixed lymphocyte reactions and autologous lymphocyte cultures.
  • Compared Fc-active (siplizumab) and Fc-silent anti-CD2 monoclonal antibodies.
  • Assessed NK cell activation, natural cytotoxicity, antibody-dependent cytotoxicity, and fratricide.

Main Results:

  • CD2 blockade without Fc gamma receptor binding inhibited NK cell activation in mixed lymphocyte reactions.
  • Siplizumab enhanced NK cell activation in both mixed lymphocyte reactions and autologous cultures due to FcγRIIIA binding.
  • CD2 blockade did not inhibit natural or antibody-dependent cytotoxicity in purified NK cells; siplizumab induced NK cell fratricide.

Conclusions:

  • Siplizumab's FcγRIIIA binding drives NK cell activation and fratricide, suggesting a mechanism for T and NK cell depletion.
  • Siplizumab demonstrates potential as a biopharmaceutical for transplantation, targeting T and NK cells with limited off-target effects.

Keywords:
CD2NK alloreactivityNK cellantibody-dependent cell-mediated cytotoxicitysiplizumabspontaneous cytotoxicity

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