title: Targeting Stereotyped B Cell Receptors from Chronic Lymphocytic Leukemia Patients with Synthetic Antigen Surrogates.
abstract: Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that haveIGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B-cells but not to healthy B-cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset.
authors: From the Departments of Chemistry.
authors: Mohosin
authors: M
authors: Sarkar
authors: The Karches Center for Chronic Lymphocytic Leukemia Research, Hofstra North Shore-LIJ School of Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030.
authors: Yun
authors: Y
authors: Liu
authors: Cancer Biology, and.
authors: Junpeng
authors: J
authors: Qi
authors: Cancer Biology, and.
authors: Haiyong
authors: H
authors: Peng
authors: From the Departments of Chemistry.
authors: Jumpei
authors: J
authors: Morimoto
authors: Cancer Biology, and Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458 and.
authors: Christoph
authors: C
authors: Rader
authors: The Karches Center for Chronic Lymphocytic Leukemia Research, Hofstra North Shore-LIJ School of Medicine, The Feinstein Institute for Medical Research, Manhasset, New York 11030.
authors: Nicholas
authors: N
authors: Chiorazzi
authors: From the Departments of Chemistry, Cancer Biology, and kodadek@scripps.edu.
authors: Thomas
authors: T
authors: Kodadek
mesh_terms: D000941:Antigens / Q000235:genetics / Q000276:immunology*; D005260:Female; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000941:Antigens; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell
keywords: Antigen Surrogate; B Cell Receptor; antibody; cancer therapy; chronic lymphocytic leukemia; combinatorial chemistry; drug discovery; drug screening; immunoglobulin G (IgG); leukemia