Antitumor immune effector mechanisms recruited by phage display-derived fully human IgG1 and IgA1 monoclonal antibodies.
We have constructed a recombinant, fully human IgA1 monoclonal antibody, UBS-54/IgA1, against the tumor-associated Ep-CAM molecule and compared its tumor-killing capacity with its IgG1 counterpart in in vitro assays. The data show that phage display-derived fully human IgA1 antibodies efficiently recruit immune effector cells that express the Fc receptor for IgA, FcalphaRI (CD89). UBS-54/IgA1-mediated killing of tumor cells by isolated polymorphonuclear cells (PMNs) and in whole blood was found to proceed without the necessity to preactivate effector cells with cytokines. In addition, the IgA1 anti-Ep-CAM human monoclonal antibody (huMab) triggered phagocytosis of tumor cells by monocyte-derived macrophages. Strikingly, simultaneous addition of IgA1 and IgG1 anti-Ep-CAM antibodies did not result in enhancement of tumor cell killing unless the effector cells were stimulated with granulocyte colony-stimulating factor. The lack of an additive effect could be attributed to an inhibitory effect of IgG on IgA-mediated tumor cell killing through binding of IgG1 to the inhibitory FcgammaRIIb receptor expressed by PMNs. These results show that IgA1 antitumor huMabs are capable of recruiting the large population of peripheral blood PMNs for tumor cell killing. This population is not effectively recruited by IgG type antibodies, currently the antibodies most frequently used for clinical application. In addition, the data suggest that a combination of IgG1 and IgA1 antitumor huMabs may collaborate in tumor cell killing in patients treated with granulocyte colony-stimulating factor.
Huls
G
G
Department of Immunology, University Hospital Utrecht, The Netherlands.
Heijnen
I A
IA
Cuomo
E
E
van der Linden
J
J
Boel
E
E
van de Winkel
J G
JG
Logtenberg
T
T
D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000276:immunology*; D003165:Complement System Proteins / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D000071858:Epithelial Cell Adhesion Molecule; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007128:Immunoglobulin Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D008264:Macrophages / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D010587:Phagocytosis; D011961:Receptors, Fc / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D014162:Transfection; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D011961:Receptors, Fc; D017452:Receptors, IgG; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D003165:Complement System Proteins