title: Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells.
abstract: Despite a wealth of information about the structure of surface membrane immunoglobulin (smIg) on chronic lymphocytic leukemia (CLL) cells, little is known about epitopes reacting with their binding sites. Probing phage-displayed peptide libraries, we identified and characterized mimetopes for Igs of 4 patients with IGHV mutated CLL (M-CLL) and 4 with IGHV unmutated CLL (U-CLL). Six of these mAbs were representatives of stereotyped B-cell receptors characteristic of CLL. We found that mimetic epitopes for U- and M-CLL Igs differed significantly. M-CLL-derived peptides exhibited better amino acid motifs, were more similar to each other, aligned more easily, and formed tighter clusters than U-CLL-derived peptides. Mono-, oligo-, and polyreactivity of peptides correlated with structural changes within antigen-binding sites of selecting M-CLL mAbs. Although M-CLL-isolated peptides and certain U-CLL mAbs bound more effectively to the selecting mAb, others were not as specific, reacting with M-CLL and U-CLL mAbs; these data suggest that in vivo structurally diverse epitopes could bind smIgs of distinct CLL clones, thereby altering survival and growth. Finally, an M-CLL-derived peptide inhibited, in a dose-dependent manner, binding of its homologous mAb to human B lymphocytes; therefore peptides that inhibit or alter the consequences of antigen-smIg interactions may represent therapeutic modalities in CLL.
authors.affiliation: The Feinstein Institute for Medical Research, North Shore-Long Island Jewish (LIJ) Health System, Manhasset, NY 11030, USA.
authors.forename: Till
authors.initials: T
authors.lastname: Seiler
authors.forename: Manuela
authors.initials: M
authors.lastname: Woelfle
authors.forename: Sophia
authors.initials: S
authors.lastname: Yancopoulos
authors.forename: Rosa
authors.initials: R
authors.lastname: Catera
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.forename: Carol
authors.initials: C
authors.lastname: Moreno
authors.forename: Marcela
authors.initials: M
authors.lastname: Torres
authors.forename: Santanu
authors.initials: S
authors.lastname: Paul
authors.forename: Hartmut
authors.initials: H
authors.lastname: Dohner
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Kaufman
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.forename: Charles C
authors.initials: CC
authors.lastname: Chu
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D032701:Biomimetics; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D019151:Peptide Library; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D010446:Peptide Fragments; D019151:Peptide Library; D011947:Receptors, Antigen, B-Cell
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