title: In vivo characterization of bioconjugate B cell toleragens with specificity for autoantibodies in antiphospholipid syndrome.
abstract: This study investigated the use of well-defined bioconjugate molecules to suppress antigen-specific B cell responses to domain I (DI) of human beta(2)-glycoprotein I (beta(2)GPI) in rats. DI is the dominant target of pathogenic autoimmune antibodies in patients with antiphospholipid syndrome (APS), a disease characterized by antibody-mediated thromboembolic events. Rats primed with DI conjugated to keyhole limpet hemocyanin (DI-KLH) were rendered tolerant to subsequent antigen challenge by treatment with multivalent conjugates of DI. Antibodies to DI were suppressed 89-96% with intravenous doses of 500 micro g, and reductions were paralleled by decreases in splenic antigen-specific antibody-forming cells (AFC). Suppression was achieved with a variety of conjugates having two to four copies of DI and circulating half-lives of 2.6-8.7 h. Antibodies to KLH were not suppressed, indicating the specificity of the approach. These results establish the basis for further development of therapeutic B cell toleragens to suppress pathogenic antibodies in APS and other autoimmune diseases.
authors.affiliation: La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, CA 92121, USA. keith.cockerill@ljpc.com
authors.forename: Keith A
authors.initials: KA
authors.lastname: Cockerill
authors.forename: Eric
authors.initials: E
authors.lastname: Smith
authors.forename: David S
authors.initials: DS
authors.lastname: Jones
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Branks
authors.forename: Merle
authors.initials: M
authors.lastname: Hayag
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Victoria
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Linnik
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Campbell
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001682:Biological Availability; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006023:Glycoproteins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D006433:Hemocyanins / Q000737:chemistry / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D007165:Immunosuppression Therapy / Q000379:methods*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008958:Models, Molecular; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D013154:Spleen / Q000276:immunology; D014611:Vaccination; D053482:beta 2-Glycoprotein I
chemical_list: D000906:Antibodies; D017152:Antibodies, Antiphospholipid; D001323:Autoantibodies; D006023:Glycoproteins; D018796:Immunoconjugates; D011994:Recombinant Proteins; D053482:beta 2-Glycoprotein I; D011092:Polyethylene Glycols; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin