title: A chemically defined, toleragen-based approach for targeting anti-beta2-glycoprotein I antibodies.
abstract: Antiphospholipid syndrome is characterized by a prothrombotic state and the presence of beta2-glycoprotein I (beta2-GPI)-dependent antiphospholipid antibodies. The feasibility of a B cell tolerance-based approach for specific reduction of anti-beta2-GPI antibodies was investigated. Anti-beta2-GPI antibodies isolated from a patient with antiphospholipid syndrome were used to screen peptide libraries expressed in phage, resulting in the identification of a phage that specifically bound anti-beta2-GPI antibodies. The phage-displayed peptide was identified and chemically optimized to generate a synthetic 14-mer peptide with an internal thioether linkage (LJP 685) that retained the binding profile of the original phage. LJP 685 was conjugated to a defined, non-immunogenic organic platform to generate a tetravalent presentation of LJP 685 for use as a toleragen. Tetravalent LJP 685 induced a dose-dependent reduction in antibody levels in mice previously immunized and boosted with LJP 685 coupled to the carrier keyhole limpet hemocyanin. These experiments support the technical feasibility of a tolerance-based approach for reducing anti-beta2-GPI antibodies in vivo.
authors.affiliation: La Jolla Pharmaceutical Company, San Diego, CA 92121, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Iverson
authors.forename: D S
authors.initials: DS
authors.lastname: Jones
authors.forename: D
authors.initials: D
authors.lastname: Marquis
authors.forename: M D
authors.initials: MD
authors.lastname: Linnik
authors.forename: E J
authors.initials: EJ
authors.lastname: Victoria
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017153:Antibodies, Anticardiolipin / Q000096:biosynthesis / Q000276:immunology* / Q000302:isolation & purification; D000918:Antibody Specificity; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000628:therapy*; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D001402:B-Lymphocytes / Q000276:immunology*; D001435:Bacteriophages / Q000235:genetics; D002846:Chromatography, Affinity; D017635:Clonal Anergy; D003888:Desensitization, Immunologic; D000939:Epitopes / Q000276:immunology* / Q000302:isolation & purification; D005240:Feasibility Studies; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D010456:Peptides, Cyclic / Q000235:genetics / Q000276:immunology*; D053482:beta 2-Glycoprotein I
chemical_list: D017153:Antibodies, Anticardiolipin; D001324:Autoantigens; D000939:Epitopes; D006023:Glycoproteins; C117701:LJP 685; D009841:Oligonucleotides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D053482:beta 2-Glycoprotein I