PDL241, a novel humanized monoclonal antibody, reveals CD319 as a therapeutic target for rheumatoid arthritis

Jacky Woo,Karen Lin,Elia Breedveld,Vladimir Vexler,Debra Chao,Shiming Ye,Jianmin Li,Irene Tang,Debbie A Law,Gary C Starling,Hakju Kwon,Nicole A Belmar,Taymar Hartman,Michel Pm Vierboom,Bert A ‘T Hart

doi:10.1186/ar4400

Abstract

IntroductionTargeting 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.MethodsPDL241, 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.ResultsPDL241 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.ConclusionsThe activity of PDL241 in both in vitro and in vivo models highlights the potential of CD319 as a therapeutic target in RA.

Highlights

Targeting the CD20 antigen has been a successful therapeutic intervention in the treatment of rheumatoid arthritis (RA)
We investigated the expression of CD319 in RA tissues, and generated PDL241, a humanized monoclonal antibody, to target cells expressing CD319
Expression of CD319 in RA synovium To identify the immune cell subsets that co-express CD319 in RA synovium, formalin fixed paraffin embedded (FFPE) synovial tissues from 26 RA subjects were stained with a monoclonal antibody (mAb) to CD319 and various hematopoietic cell markers

Summary

Introduction

Targeting the CD20 antigen has been a successful therapeutic intervention in the treatment of rheumatoid arthritis (RA). 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. Patients who become refractory to anti-TNF therapy may be treated with agents that target the IL-6 pathway (tocilizumab, binding the IL-6 receptor), prevent T cell costimulation (abatacept, which binds CD80 and CD86 [3]) or deplete B cells from the circulation (anti-CD20 mAb rituximab [4]). The presence of late stage plasmablasts as a marker of resistance in active RA patients non-responsive to anti-CD20 therapy [7] illustrates the need for therapies targeted against plasmablasts and plasma cells. Previous studies have demonstrated the expression of the cell surface glycoprotein CD319 on plasma cells [9], which became the focus of the current study

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