title: Multivalent thioether-peptide conjugates: B cell tolerance of an anti-peptide immune response.
abstract: Antibodies which bind beta2-glycoprotein I (beta2GPI) are associated with antiphospholipid syndrome. Synthetic peptide mimotopes have been discovered which compete with beta2GPI for binding to selected anti-beta2GPI. A thiol-containing linker was attached to the N-terminus of two cyclic thioether peptide mimotopes, peptides 1a and 1b. The resulting peptides, with linker attached, were reacted with two different haloacetylated platforms to prepare four tetravalent peptide-platform conjugates to be tested as B cell toleragens. The linker-containing peptides were reacted with maleimide-derivatized keyhole limpet hemocyanin (KLH) to provide peptide-KLH conjugates. Peptides 1a and 1b were also modified by acylation with 3-(4'-hydroxyphenyl)propionic acid N-hydroxysuccinimidyl ester. The resulting hydroxyphenyl peptides were radioiodinated and used to measure anti-peptide antibody levels. The KLH conjugates were used to immunize mice to generate an anti-peptide immune response. The immunized mice were treated with the conjugates or saline solution and boosted with the appropriate peptide-KLH conjugate. Three of the four conjugates suppressed the formation of anti-peptide antibody. The stabilities of the conjugates in mouse serum were measured, and the relative stabilities did not correlate with ability to suppress antibody formation.
authors.affiliation: La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, California 92121, USA. dave.jones@ljpc.com
authors.forename: D S
authors.initials: DS
authors.lastname: Jones
authors.forename: S M
authors.initials: SM
authors.lastname: Coutts
authors.forename: C A
authors.initials: CA
authors.lastname: Gamino
authors.forename: G M
authors.initials: GM
authors.lastname: Iverson
authors.forename: M D
authors.initials: MD
authors.lastname: Linnik
authors.forename: M E
authors.initials: ME
authors.lastname: Randow
authors.forename: H T
authors.initials: HT
authors.lastname: Ton-Nu
authors.forename: E J
authors.initials: EJ
authors.lastname: Victoria
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D006433:Hemocyanins / Q000737:chemistry / Q000276:immunology; D007108:Immune Tolerance; D007109:Immunity; D051379:Mice; D010455:Peptides / Q000737:chemistry* / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013440:Sulfides / Q000737:chemistry* / Q000276:immunology
chemical_list: D010455:Peptides; D013438:Sulfhydryl Compounds; D013440:Sulfides; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin