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PMID: 18024795 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement.

Blood ·Vol. 111 ·No. 3 ·2008-02-01 ·Pages 1456-63

Wang SY, Racila E, Taylor RP, Weiner GJ

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) and complement fixation both appear to play a role in mediating antitumor effects of monoclonal antibodies (mAbs), including rituximab. We evaluated the relationship between rituximab-induced complement fixation, natural killer (NK)-cell activation, and NK cell-mediated ADCC. Down-modulation of NK- cell CD16 and NK-cell activation induced by rituximab-coated target cells was blocked by human serum but not heat-inactivated serum. This inhibition was also observed in the absence of viable target cells. C1q and C3 in the serum were required for these inhibitory effects, while C5 was not. An antibody that stabilizes C3b on the target cell surface enhanced the inhibition of NK-cell activation induced by rituximab-coated target cells. Binding of NK cells to rituximab-coated plates through CD16 was inhibited by the fixation of complement. C5-depleted serum blocked NK cell-mediated ADCC. These data suggest that C3b deposition induced by rituximab-coated target cells inhibits the interaction between the rituximab Fc and NK-cell CD16, thereby limiting the ability of rituximab-coated target cells to induce NK activation and ADCC. Further studies are needed to define in more detail the impact of complement fixation on ADCC, and whether mAbs that fail to fix complement will be more effective at mediating ADCC.

MeSH Terms
Antibodies, Monoclonal/pharmacology Antibodies, Monoclonal, Murine-Derived Antibody-Dependent Cell Cytotoxicity/drug effects,immunology Antigens, Protozoan/immunology Antigens, Surface/immunology Cell Survival/drug effects Coculture Techniques Complement C1q/immunology Complement C3b/immunology Down-Regulation/drug effects Hot Temperature Humans Intercellular Adhesion Molecule-1/metabolism Killer Cells, Natural/cytology,drug effects,immunology,metabolism Lymphocyte Activation/drug effects,immunology Macrophage-1 Antigen/metabolism Protein Binding Receptors, IgG/metabolism Rituximab Serum Up-Regulation/drug effects
Chemicals
Antibodies, Monoclonal Antibodies, Monoclonal, Murine-Derived Antigens, Protozoan Antigens, Surface C5 phagosomal antigen, Paramecium multimicronucleatum Macrophage-1 Antigen Receptors, IgG Intercellular Adhesion Molecule-1 Rituximab Complement C1q Complement C3b
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Wang Siao-Yi
Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
Racila Emilian
Taylor Ronald P
Weiner George J
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2007-02-074716
Published
2008-02-01
Epub
2007-00-16
Pages
1456-63
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2214766
Subset
IM
Grants
NCI NIH HHS · P50 CA097274 · United States
NIGMS NIH HHS · T32 GM007337 · United States
NCI NIH HHS · P50 CA97274 · United States
External Links
PubMed source DOI: 10.1182/blood-2007-02-074716 PMC Full Text View journal details
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