title: Chimeric IgA antibodies against HLA class II effectively trigger lymphoma cell killing.
abstract: Antibodies against human leukocyte antigen (HLA) class II, such as 1D10 or Lym-1, are currently being evaluated for the treatment of B-cell lymphomas. Previous studies have demonstrated that, in addition to IgG Fc receptors, the human myeloid IgA receptor (Fc(alpha)RI, CD89) also effectively triggered tumor cell killing. Therefore, we used the variable light and heavy chain sequences from another murine anti-HLA class II hybridoma, F3.3, to generate a panel of chimeric human/mouse antibodies, including human immunoglobulin A1 (IgA1), IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody production was accomplished by stable transfection of baby hamster kidney cells, and binding activity and specificity were confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. All constructs demonstrated similar binding to HLA class II. Functional studies revealed that chimeric IgG1, IgA1, and IgA2 triggered similar levels of tumor cell lysis. Analyses of effector populations, however, demonstrated that killing by chimeric IgG1 constructs was triggered mainly by human mononuclear cells and complement, while IgA1 and IgA2 mediated effective lysis by polymorphonuclear neutrophils. Importantly, IgG1 and both IgA isotypes were equally effective at killing freshly isolated human chronic lymphocytic leukemia cells. Chimeric IgA antibodies against HLA class II may constitute attractive reagents for lymphoma therapy.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine III, University Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dechant
authors.forename: Gestur
authors.initials: G
authors.lastname: Vidarsson
authors.forename: Bernhard
authors.initials: B
authors.lastname: Stockmeyer
authors.forename: Roland
authors.initials: R
authors.lastname: Repp
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.forename: Martin
authors.initials: M
authors.lastname: Gramatzki
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van De Winkel
authors.forename: Thomas
authors.initials: T
authors.lastname: Valerius
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000473:pathology; D002460:Cell Line; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D007668:Kidney / Q000166:cytology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology; D008223:Lymphoma / Q000473:pathology*; D008647:Mesocricetus; D051379:Mice; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D006684:HLA-DR Antigens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins