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.
Highlights
We have previously shown that 3F8, a murine IgG, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill invitro and invivo
3F8 IS A MURINE IgG, monoclonal antibody (MoAb) that is well-suited for targeted immunotherapy of cancer because (1) its ganglioside G, target antigen is highly restricted to neuroectodermal tissues and is genetically stable's2; (2) it has excellent tumor localization in patients[3]; and (3) in vitro, it mediates human tumor cell destruction by human complement and by human lymphocytes, cultured monocytes, and polymorphonuclear leukocytes (PMN).4-7This constellation of features, which may account for regressions of GD2+( ) tumors in patients treated with 3F8,8 has been documented in very few MoAbs
leukocyte adhesion deficiency (LAD) PMN, which were confirmed by immunophenotyping to be devoid of the entire CD11/ CD18 complex, mounted no detectable antibody-dependent cellular cytotoxicity (ADCC) (Table 1)
Summary
We have previously shown that 3F8, a murine IgG, monoclonal antibody (MoAb) specific for the ganglioside GD2, mediates tumor cell kill invitro and invivo. 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 PMNADCC) required C D l lb, CDllc, FcRII, and the PI-linked FcRIII. In this clinically relevant system, GM-CSF enhancement of antitumor PMN ADCC correlated with increased expression of C D l l /CD18 molecules. Presented in part at the 32nd Annual Meeting of the American Society of Hematology,Boston, MA, November 28-December 4, 1990. PMN ADCC of human tumor cells mediated by heterologous antibodies are few in n~mber.'~-O'' ther studies of antitumor PMN ADCC have used heterologous antibodies and nonhuman, usually lymphohematopoietic, target^.'^.,^ The cytotoxic mechanisms in these model systems may differ from those operative in PMN ADCC of human solid tumor cells that are large in size, and may not be readily phagocytosed by PMN, but are relatively resistant to reactive oxygen
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