Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy.
Three different classes of Fc receptors for IgG (Fc gamma R) are currently distinguished in humans, of which polymorphonuclear phagocytes (PMN) normally express both low-affinity receptor classes--Fc gamma RII (CD32) and Fc gamma RIII (CD16). During therapy with granulocyte colony-stimulating factor (G-CSF), neutrophils from patients with various malignancies and different hematologic disorders were found to additionally express high levels of the receptor with high affinity for IgG (Fc gamma RI; CD64). For these patients, the relative fluorescence intensity (rFI) for Fc gamma RI was 5.3 (range, 1.7 to 10.3; n = 19), compared with 1.0 (range, 1.0 to 1.1; n = 8) for healthy donors. The expression of Fc gamma RI during G-CSF therapy could be confirmed by using a panel of six CD64-specific antibodies, and by showing mRNA for Fc gamma RI. So far, three genes for Fc gamma RI have been identified, encoding four distinct transcription products. By reverse transcriptase-polymerase chain reaction technology, transcripts for both membrane-associated isoforms (hFc gamma RIa and hFc gamma RIb2) could be detected. The functional activity of Fc gamma RI on PMN during G-CSF therapy was shown by measuring binding of monomeric human IgG and antibody-dependent cellular cytotoxicity (ADCC). Thus, Fc gamma RI-positive neutrophils displayed enhanced ADCC activity to glioma (A1207), squamous cell (A431), and ovarian (SK-ov3) carcinoma cell lines. The involvement of Fc gamma RI in this increased cytotoxic activity was shown by blocking Fc gamma receptors with monoclonal antibodies, and by using F(ab')2 x F(ab')2-bispecific antibodies with specificities against tumor-related antigens and Fc gamma RI, resulting in solely Fc gamma RI-mediated cytotoxicity. Therapeutically, this additional Fc receptor on PMN may increase the efficacy of experimental antibody therapy.
Valerius
T
T
Department of Medicine III, University of Erlangen-Nürnberg, Germany.
Repp
R
R
de Wit
T P
TP
Berthold
S
S
Platzer
E
E
Kalden
J R
JR
Gramatzki
M
M
van de Winkel
J G
JG
D000920:Antibody-Dependent Cell Cytotoxicity; D001483:Base Sequence; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D009504:Neutrophils / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D012334:RNA, Neoplasm / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D009838:Oligodeoxyribonucleotides; D012334:RNA, Neoplasm; D017452:Receptors, IgG; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor