title: Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation.
abstract: 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 cell-surface 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 downregulated the Th1 response, as seen by a 50-95% reduction in secreted IL-2 and IFN-gamma. 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.
authors.affiliation: Alexion Antibody Technologies, Incorporated, San Diego, CA 92121, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: McWhirter
authors.forename: Anke
authors.initials: A
authors.lastname: Kretz-Rommel
authors.forename: Alan
authors.initials: A
authors.lastname: Saven
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Potter
authors.forename: C Ian
authors.initials: CI
authors.lastname: Mockridge
authors.forename: E Prenn
authors.initials: EP
authors.lastname: Ravey
authors.forename: Fenghua
authors.initials: F
authors.lastname: Qin
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Bowdish
mesh_terms: D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000951:Antigens, Neoplasm; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000378:metabolism; D013058:Mass Spectrometry; D009000:Monocytes / Q000378:metabolism; D019151:Peptide Library; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D018417:Th1 Cells; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016207:Cytokines; D007128:Immunoglobulin Fragments; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D019151:Peptide Library