Journal Article

Antibodies Selected from Combinatorial Libraries Block a Tumor Antigen That Plays a Key Role in Immunomodulation

Ravey, E. Prenn, Qin, Fenghua, Bowdish, Katherine S., Kretz-Rommel, Anke, Mockridge, C. Ian, Maruyama, Toshiaki, Potter, Kathleen N., McWhirter, John R., Saven, Alan

2006

Overview

We searched for cell-surface-associated proteins overexpressed on B cell chronic lymphocytic leukemia (CLL) to use as therapeutic antibody targets. Antibodies binding the immunosuppressive molecule CD200 were identified by cell panning of an antibody phage display library derived from rabbits immunized with primary CLL cells. B cells from 87 CLL patients exhibited 1.6- to 5.4-fold cellsurface up-regulation of CD200 relative to normal B cells. An effect of increased CD200 expression by CLL cells on the immune system was evaluated in mixed lymphocyte reactions. Addition of primary CLL but not normal B cells to macrophages and T cells down-regulated the Th1 response, as seen by a 50-95% reduction in secreted IL-2 and IFN-γ. Antibodies to CD200 prevented downregulation of the Th1 response in most B cell CLL samples evaluated, indicating abrogation of the CD200/CD200R interaction can be sufficient to restore the Th1 response. A disease-progression-associated shift of the immune response from Th1 to Th2 has been observed in numerous cancers. Because this cytokine shift is also believed to promote the induction of regulatory T cells, reverting the immune response to Th1 through direct targeting of the cancer cells may provide therapeutic benefits in CLL by encouraging a cytotoxic T cell response.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Antibodies / Antibodies - chemistry / Antibodies, Monoclonal - chemistry / Antigens / Antigens, Neoplasm / B lymphocytes / B-Lymphocytes - metabolism / Bacteriophages / Biological Sciences / Cell Line / Cell Line, Tumor / Cell lines / Cell Membrane - metabolism / Cell Separation / Chronic lymphocytic leukemia / Cytokines / Cytokines - metabolism / Dendritic cells / Dendritic Cells - cytology / Down-Regulation / Enzyme-Linked Immunosorbent Assay / Flow Cytometry / Humans / Immune response / Immune system / Immunization / Immunoglobulin Fragments - chemistry / Immunoglobulins / Immunology / Immunoprecipitation / Immunosuppressive Agents - pharmacology / Immunotherapy - methods / Interleukin-2 - metabolism / Leukemia / Leukemia, Lymphocytic, Chronic, B-Cell - genetics / Leukemia, Lymphocytic, Chronic, B-Cell - immunology / Leukocytes, Mononuclear - metabolism / Libraries / Lymphocyte Culture Test, Mixed / Lymphocytes / Lymphocytes - immunology / Macrophages - metabolism / Mass Spectrometry / Monocytes - metabolism / Peptide Library / Proteins / T lymphocytes / T-Lymphocytes, Regulatory - cytology / Th1 Cells / Th2 Cells - immunology / Tumors / Up regulation