title: Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells.
abstract: The Human Combinatorial Antibody Library (HuCAL) was screened for antibodies specific to human leukocyte antigen-DR (HLA-DR) that induce programmed death of lymphoma/leukemia cells expressing the target antigen. The active Fab fragments were affinity-matured, and engineered to IgG(4) antibodies of sub-nanomolar affinity. The antibodies exhibited potent in vitro tumoricidal activity on several lymphoma and leukemia cell lines and on chronic lymphocytic leukemia patient samples. They were also active in vivo in xenograft models of non-Hodgkin lymphoma. Cell death occurred rapidly, without the need for exogenous immunological effector mechanisms, and was selective to activated/tumor-transformed cells. Although the expression of HLA-DR on normal hematopoietic cells is a potential safety concern, the antibodies caused no long-lasting hematological toxicity in primates, in vivo. Such monoclonal antibodies offer the potential for a novel therapeutic approach to lymphoid malignancies.
authors.affiliation: GPC Biotech AG, Martinsried/Munich, Germany. zoltan.nagy@gpc-biotech.com
authors.forename: Zoltan A
authors.initials: ZA
authors.lastname: Nagy
authors.forename: Bernd
authors.initials: B
authors.lastname: Hubner
authors.forename: Corinna
authors.initials: C
authors.lastname: Löhning
authors.forename: Robert
authors.initials: R
authors.lastname: Rauchenberger
authors.forename: Silke
authors.initials: S
authors.lastname: Reiffert
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Thomassen-Wolf
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahn
authors.forename: Sigmar
authors.initials: S
authors.lastname: Leyer
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schier
authors.forename: Angelika
authors.initials: A
authors.lastname: Zahradnik
authors.forename: Christoph
authors.initials: C
authors.lastname: Brunner
authors.forename: Kurt
authors.initials: K
authors.lastname: Lobenwein
authors.forename: Benno
authors.initials: B
authors.lastname: Rattel
authors.forename: Michael
authors.initials: M
authors.lastname: Stanglmaier
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Mark
authors.initials: M
authors.lastname: Wing
authors.forename: Steve
authors.initials: S
authors.lastname: Anderson
authors.forename: Matt
authors.initials: M
authors.lastname: Dunn
authors.forename: Titus
authors.initials: T
authors.lastname: Kretzschmar
authors.forename: Michael
authors.initials: M
authors.lastname: Tesar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D000915:Antibody Affinity; D000970:Antineoplastic Agents / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis; D006684:HLA-DR Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007167:Immunotherapy; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000473:pathology* / Q000503:physiopathology; D008252:Macaca fascicularis; D051379:Mice; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006684:HLA-DR Antigens; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins