title: PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis.
abstract: BACKGROUND
  Targeting the CD20 antigen has been a successful therapeutic intervention in the treatment of rheumatoid arthritis (RA). However, in some patients with an inadequate response to anti-CD20 therapy, a persistence of CD20- plasmablasts is noted. The strong expression of CD319 on CD20- plasmablast and plasma cell populations in RA synovium led to the investigation of the potential of CD319 as a therapeutic target.
  
  
  METHODS
  PDL241, a novel humanized IgG1 monoclonal antibody (mAb) to CD319, was generated and examined for its ability to inhibit immunoglobulin production from plasmablasts and plasma cells generated from peripheral blood mononuclear cells (PBMC) in the presence and absence of RA synovial fibroblasts (RA-SF). The in vivo activity of PDL241 was determined in a human PBMC transfer into NOD scid IL-2 gamma chain knockout (NSG) mouse model. Finally, the ability of PDL241 to ameliorate experimental arthritis was evaluated in a collagen-induced arthritis (CIA) model in rhesus monkeys.
  
  
  RESULTS
  PDL241 bound to plasmablasts and plasma cells but not naïve B cells. Consistent with the binding profile, PDL241 inhibited the production of IgM from in vitro PBMC cultures by the depletion of CD319+ plasmablasts and plasma cells but not B cells. The activity of PDL241 was dependent on an intact Fc portion of the IgG1 and mediated predominantly by natural killer cells. Inhibition of IgM production was also observed in the human PBMC transfer to NSG mouse model. Treatment of rhesus monkeys in a CIA model with PDL241 led to a significant inhibition of anti-collagen IgG and IgM antibodies. A beneficial effect on joint related parameters, including bone remodeling, histopathology, and joint swelling was also observed.
  
  
  CONCLUSIONS
  The activity of PDL241 in both in vitro and in vivo models highlights the potential of CD319 as a therapeutic target in RA.
authors.forename: Jacky
authors.initials: J
authors.lastname: Woo
authors.forename: Michel P M
authors.initials: MP
authors.lastname: Vierboom
authors.forename: Hakju
authors.initials: H
authors.lastname: Kwon
authors.forename: Debra
authors.initials: D
authors.lastname: Chao
authors.forename: Shiming
authors.initials: S
authors.lastname: Ye
authors.forename: Jianmin
authors.initials: J
authors.lastname: Li
authors.forename: Karen
authors.initials: K
authors.lastname: Lin
authors.forename: Irene
authors.initials: I
authors.lastname: Tang
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Belmar
authors.forename: Taymar
authors.initials: T
authors.lastname: Hartman
authors.forename: Elia
authors.initials: E
authors.lastname: Breedveld
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vexler
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Law
authors.forename: Gary C
authors.initials: GC
authors.lastname: Starling
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D000917:Antibody Formation / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D007150:Immunohistochemistry; D008253:Macaca mulatta; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010950:Plasma Cells / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007136:Immunoglobulins; D011971:Receptors, Immunologic; C448987:SLAMF7 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family