title: MEDI-551 Treatment Effectively Depletes B Cells and Reduces Serum Titers of Autoantibodies in Mice Transgenic for Sle1 and Human CD19.
abstract: OBJECTIVE
  To evaluate treatment with MEDI-551, a humanized anti-human CD19 monoclonal antibody, in a model of autoimmunity involving mice transgenic (Tg) for Sle1 and human CD19 (hCD19).
  
  
  METHODS
  Sle1.hCD19-Tg mice were given either a single intravenous dose of MEDI-551 or repeated doses of MEDI-551 biweekly for up to 12 weeks. The numbers of B cells in the blood, spleen, and bone marrow were determined by flow cytometry assay. In the spleen and bone marrow, the number of IgM- and IgG-specific antibody-secreting cells (ASCs) and the number of ASCs specific for anti-double-stranded DNA (anti-dsDNA) were determined by enzyme-linked immunospot assay. Serum autoantibody and total immunoglobulin levels were determined by enzyme-linked immunosorbent assay, and levels of inflammatory proteins were tested using a multianalyte profiling platform.
  
  
  RESULTS
  MEDI-551 treatment of Sle1.hCD19-Tg mice resulted in effective and sustained B cell depletion throughout the duration of the experiment. The frequency of IgM and IgG ASCs in the spleen was reduced by ≥90%, whereas in the bone marrow, the total ASC frequency was not changed. Levels of autoantibodies specific for dsDNA as well as antihistone and antinuclear antibodies were each reduced by 40-80%, but total serum immunoglobulin levels were largely unchanged at the end of 12 weeks of treatment.
  
  
  CONCLUSIONS
  These findings highlight the ability of MEDI-551 to deplete B cells and ASCs in autoimmune Sle1.hCD19-Tg mice. MEDI-551 treatment resulted in a robust reduction of autoantibodies but had minimal effect on total serum immunoglobulins. Thus, the novel ability of MEDI-551 to remove a broad range of B cells as well as to lower most disease-driving autoantibodies in an autoimmune disease mouse model warrants continued research. Several clinical studies to explore the safety and activity of MEDI-551 in autoantibody-associated autoimmune diseases are ongoing.
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gallagher
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Isharat
authors.initials: I
authors.lastname: Yusuf
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Tom M
authors.initials: TM
authors.lastname: McCaughtry
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Sean
authors.initials: S
authors.lastname: Turman
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Roland
authors.initials: R
authors.lastname: Kolbeck
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.affiliation: MedImmune, Gaithersburg, Maryland.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000921:Antibody-Producing Cells / Q000187:drug effects / Q000276:immunology; D018941:Antigens, CD19 / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000187:drug effects* / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000166:cytology / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C000609745:inebilizumab; D004247:DNA