Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity

Abstract

We have previously shown that 3F8, a murine IgG3, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill in vitro and in vivo. We now describe receptor requirements of polymorphonuclear leukocytes (PMN) in 3F8-mediated cytotoxicity (ADCC) of human GD2 (+) melanoma and neuroblastoma cell lines. PMN from a child with leukocyte adhesion deficiency (LAD) were devoid of CD11/CD18 adhesion molecules and mounted no detectable ADCC. MoAb to CD11b, CD11c, and CD18 each efficiently blocked ADCC by normal PMN. In contrast, a panel of different MoAbs to CD11a had no significant inhibitory effect on ADCC, a finding consistent with the low-to-absent expression of the CD11a ligand, intercellular adhesion molecule-1, on the target cells. Granulocyte-macrophage colony-stimulating factor (GM- CSF) significantly increased the expression of CD11b, CD11c, and CD18 on normal PMN, decreased the expression of Fc receptors (FcR), and enhanced ADCC by normal but not by LAD PMN. MoAbs to FcRII and FcRIII each efficiently blocked ADCC; anti-FcRI MoAb had no effect. Flow cytometry using anti-FcRII MoAb versus anti-FcRIII MoAb did not show cross competition, suggesting that inhibition of ADCC was not a steric effect resulting from FcRII proximity to FcRIII. PMN deficient in FcRIII (obtained from patients with paroxysmal nocturnal hemoglobinuria) and PMN depleted of FcRIII by treatment with elastase or phosphatidylinositol (PI)-specific phospholipase C produced low ADCC, supporting a role for the PI-liked FcRIII. Thus, optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked FcRIII. Furthermore, in this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of CD11/CD18 molecules.

Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo

“…It also induces complement mediated cytotoxicity (CMC) of NB cells, which lack decay accelerating factor CD55 8 and homologous restriction factor CD59. 9 Complement deposition on NB cells enhances ADCC through activation of the iC3b receptor on neutrophils, 10 , 11 available even after dose-intensive or myeloablative chemotherapy plus stem cell transplant, provided colony stimulating factors are given. 12 Moreover, the use of intensive chemotherapy, which is standard of care for NB to achieve clinical remission, will result in prolonged lymphopenia and immunosuppression, 13 such that patients are less likely to reject murine or chimeric MoAb.…”

Neutrophils as Orchestrators in Tumor Development and Metastasis Formation

“…Antibody dependent cell-mediated cytotoxicity (ADCC) represents another way by which neutrophils may kill tumor cells. In particular, neutrophils express several Fc receptors (FcRs), such as FcγRI (CD64), FcγRIIa (CD32), FcγRIIIa (CD16a), and FcγRIIIb (CD16b) that recognize tumor cell-specific antibodies and mediate ADCC ( 52 , 54 , 55 ). In addition, neutrophil phagocytosis of opsonized tumor cells enhances anti-tumor activity ( 56 ) as shown with human tumor cells ( 57 ).…”

Glycobiology of Neuroblastoma: Impact on Tumor Behavior, Prognosis, and Therapeutic Strategies

“…Its efficacy in treating NB was initially described in 1987 in the report of a Phase 1 trial which included patients with refractory high-risk NB ( 159 ). MAb 3F8 mediates highly efficient antibody-dependent cell-mediated cytotoxicity (ADCC) of NB in the presence of human natural killer (NK) cells and granulocytes in vitro ( 160 – 162 ). Moreover, it induces complement-mediated cytotoxicity (CMC), because NB cells lack decay-accelerating factor CD55 ( 163 ) and homologous restriction factor CD59 ( 164 ).…”