Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.


Depletion of Inducible Co-Stimulator (ICOS) Bearing T Cells Inhibits Expansion of T Follicular Helper Cells (TFH) and Prevents Disease in a Graft Versus Host Mouse Model of Scleroderma

Carlesso1,  Gianluca, Lemaire1,  Raphael, Taylor1,  Devon, Mittereder1,  Nanette, Kuta1,  Ellen, Burwell1,  Timothy, Delaney1,  Tracy

MedImmune, LLC, Gaithersburg, MD
MedImmune, Gaithersburg, MD

Purpose:

Human cluster of differentiation antigen 278, also called inducible T-cell co-stimulator (ICOS) is a T cell-specific surface antigen selectively expressed by recently activated, memory, and T follicular helper (Tfh) T cells. In this study, the function of ICOS in the pathogenesis of a graft-versus-host disease (GvHD) mouse model of scleroderma (SSc) was investigated using a glycoengineered anti-mouse ICOS MAb with enhanced antibody-dependent cellular cytotoxicity (ADCC).

Methods:

We have generated a glyco-engineered rat anti-ICOS monoclonal antibody (MAb) directed against the ligand binding domain of murine ICOS as mouse IgG2a. The antibody was produced in a fucosyltransferase 8-deficient Chinese Hamster Ovary (CHO) producer cell line (BioWa Potelligent® Technology), a procedure that generates a homogenously afucosylated antibody (anti-ICOS-aFuc) with enhanced ADCC. The activity of the afucosylated anti-mouse ICOS MAb, was evaluated in a murine GvHD model, which recapitulates key aspects of human SSc, including inflammation, fibrosis, and vasculopathy.

Results:

Dosing of the anti-ICOS-aFuc MAb reduced severity and incidence of dermal lesions when compared to isotype control MAb and control syngeneic graft. Mean clinical scores were significantly reduced in anti-ICOS-treated groups compared to isotype control MAb-treated mice, as early as 12 days post-graft (3.4-fold, p<0.002), and thereafter up to 4 weeks post graft (8.1-fold, p<0.0001). The anti-ICOS-aFuc MAb also prevented the disease-associated accumulation of TFHcells and the associated expansion of germinal center B cells and immunoglobulin secreting B cells. There were no ICOS MAb-related clinical signs or changes in body weight in animals during the study.

Conclusion:

The results from this study indicate that ICOS plays an important role in dermal pathology of murine GvHD-SSc, as depletion of ICOS+ T cells reduced the overall clinical disease score. The identification of dysregulated ICOS+ TFH cells in GvHD-SSc underscore their critical function in driving the generation of pathogenic B cells into germinal center B cells in secondary lymphoid tissues and in the differentiation of immunoglobulin secreting B cells in the skin. Importantly, treatment with the anti-mouse ICOS-aFuc MAb resulted in a significant reduction of the clinical signs of disease and represents an innovative therapeutic strategy for the treatment of T helper associated autoimmune GvHD-SSc.

To cite this abstract, please use the following information:
Carlesso, Gianluca, Lemaire, Raphael, Taylor, Devon, Mittereder, Nanette, Kuta, Ellen, Burwell, Timothy, et al; Depletion of Inducible Co-Stimulator (ICOS) Bearing T Cells Inhibits Expansion of T Follicular Helper Cells (TFH) and Prevents Disease in a Graft Versus Host Mouse Model of Scleroderma [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1065
DOI: 10.1002/art.26141

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