Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


TRA-8 (CS-1008), a Novel Anti-Arthritic Biologic Agent That Targets Macrophages with Low Toxicity.

Li1,  Jun, Hsu2,  Hui-Chen, Yang2,  PingAr, Wu2,  Qi, Mountz1,  John D.

Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL

Background:

Macrophages contribute to joint inflammation and destruction in both the acute and chronic phases of rheumatoid arthritis (RA). However, biologic agents that can selectively eliminate pathogenic macrophages in RA have not been identified. Death receptor 5 (DR5) is a pro-apoptotic protein, which mediates apoptosis upon binding to a novel anti-human DR5 antibody, TRA-8 (humanized, CS-1008). We have found that macrophages isolated from both synovium and peripheral blood of RA patients express DR5 and are susceptible to TRA-8 mediated killing. The purpose of this study is to use a humanized DR5 transgenic mouse to evaluate the therapeutic efficacy of TRA-8 by eliminating pathogenic macrophages in a chicken collagen II (CII)-induced arthritis (CIA) model.

Methods:

A chimeric human/mouse DR5 transgenic mouse was generated using a 3kb mouse promoter/Floxed STOP/humanized mouse DR5 construct in which the extracellular domain of mouse DR5 was replaced by the human counterpart. Macrophages specific expression of chimeric DR5 is achieved by crossing the DR5 mice with lysozyme M-Cre mice. Arthritis was induced by AdIL-17 at day -2 plus intradermal injection of CII in CFA/IFA on day 0 and day 30. TRA-8 (0.2 mg per mouse) was administrated I.V. every 3–7 days starting on day 0 (early treatment) or on day 30 (late treatment) until mice were sacrificed 3 months after the primary CII injection. Enumeration of macrophages before and after CII injection was determined by FACS analysis. In vivo joint macrophage activity was quantitated using an infrared cathespin B in vivo imaging analysis. Clinical scoring and histologic assessments were performed to evaluate the severity of arthritis.

Results:

There was a higher percentage of CD11b+ macrophages in the spleen of CII immunized mice (12.08%) compared to naïve mice (2.5%). Chimeric DR5 is highly expressed on CD11b+ macrophage. TRA-8 treatment resulted in 60% and 48% reduction of CD11bhigh activated macrophages isolated from the spleen for early and late TRA-8 treatment, respectively. For both early and late TRA-8 treatments, joint histopathology showed a significantly decreased severity of inflammatory cell infiltration, synovial hyperplasia, cartilage damage, and bone erosion. Immunohistochemistry staining further demonstrated a dramatically reduced Mac-3+ macrophages in the synovium after TRA-8 treatment. In vivo live imaging of joints revealed that there was a significantly decreased macrophage activation-induced cathepsin B activity in chimeric DR5 Tg mice that received TRA-8 treatment. The arthritis clinical scores were highly correlated with the abundance of macrophages in synovium and spleen. Neither systematic toxicities nor increased incidences of infections and malignancies were found in TRA-8 treated DR5 Tg mice.

Summary:

This study demonstrated that TRA-8 (CS-1008) is a novel anti-arthritic biologic agent with high safety. Importantly, since the DR5 molecule is expressed on macrophages, our results suggest that TRA-8 can be developed into a novel therapy to either prevent the onset or suppress established arthritis via elimination of macrophages.

To cite this abstract, please use the following information:
Li, Jun, Hsu, Hui-Chen, Yang, PingAr, Wu, Qi, Mountz, John D.; TRA-8 (CS-1008), a Novel Anti-Arthritic Biologic Agent That Targets Macrophages with Low Toxicity. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1135
DOI: 10.1002/art.28902

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