Fully human, HLA-DR-specific monoclonal antibodies efficiently induce programmed death of malignant lymphoid cells

• Published in: Nature medicine Vol. 8; no. 8; pp. 801 - 807
• Main Authors: Nagy, Zoltan A, Hubner, Bernd, Löhning, Corinna, Rauchenberger, Robert, Reiffert, Silke, Thomassen-Wolf, Elisabeth, Zahn, Stefan, Leyer, Sigmar, Schier, Eva M, Zahradnik, Angelika, Brunner, Christoph, Lobenwein, Kurt, Rattel, Benno, Stanglmaier, Michael, Hallek, Michael, Wing, Mark, Anderson, Steve, Dunn, Matt, Kretzschmar, Titus, Tesar, Michael
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-08-2002
• Subjects: Analysis; Animals; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Antibody Affinity; Antigens; Antineoplastic Agents - immunology; Antineoplastic Agents - metabolism; Apoptosis; Cell death; Hematology; HLA-DR Antigens - immunology; HLA-DR Antigens - metabolism; Humans; Immunoglobulin Fab Fragments - genetics; Immunoglobulin Fab Fragments - immunology; Immunoglobulin Fab Fragments - metabolism; Immunoglobulin G - genetics; Immunoglobulin G - immunology; Immunoglobulin G - metabolism; Immunology; Immunotherapy; Leukemia; Leukocytes; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphoma; Lymphoma - pathology; Lymphoma - physiopathology; Lymphomas; Macaca fascicularis; Mice; Monoclonal antibodies; Mortality; Physiological aspects; Protein Binding; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; Tumor Cells, Cultured; Germany
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm736

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.