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AB0071 Characterization of NNC141-0100, a therapeutic antibody targeting inhibitory CD94/NKG2A receptors expressed in inflamed joints of rheumatoid arthritis patients
  1. V. Pascal1,
  2. Y. Sundström2,
  3. A. Fasth2,
  4. V. Malmström2,
  5. L. Berg2,
  6. P.H. Kvist3,
  7. P. Spee1,
  8. E.D. Galsgaard3
  1. 1Department of Translational Immunology, Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark
  2. 2Department of Medicine, Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden
  3. 3Department of Histology, Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark

Abstract

Background CD94/NKG2A+ CD56bright Natural Killer (NK) cells represent the majority of NK cells in synovial fluid (SF) of Rheumatoid Arthritis (RA) patients and were proposed to exert an immunoregulatory role [1]. Prophylactic treatment with anti-NKG2A antibody fragment F(ab)’2 in murine collagen-induced arthritis reduced disease development by activating NK cells through blockade of its inhibitory receptor CD94/NKG2A [2]. Novo Nordisk A/S has generated an antagonistic, humanized anti-human NKG2A monoclonal antibody NNC141-0100 that blocks interaction between CD94/NKG2A and its ligand HLA-E.

Objectives The aim of this study was to characterize the binding specificity of NNC141-0100 and the expression pattern of its target, the CD94/NKG2A receptors, in peripheral blood (PB), SF and/or synovial tissue from RA patients and healthy donors (HD).

Methods CD94/NKG2A and HLA-E expression was investigated using flow cytometry, immunohistochemistry, digital image analysis and double-immunofluorescence (DIF) staining.

Results In PB and SF from HD or RA patients, NNC141-0100 binding correlated with expression of CD94/NKG2A as detected by another anti-NKG2A mAb, and was restricted to subsets of NK and T cells. We observed a similar distribution of CD94/NKG2A on PB lymphocytes from HD and RA patients where ∼50% of NK cells expressed CD94/NKG2A. In contrast, the majority (>90%) of NK cells in RA SF were CD94/NKG2A+, confirming the previously reported disease-associated accumulation of CD94/NKG2A+ NK cells in RA SF [1]. CD94/NKG2A+ distribution on T cells was similar in PB from HD and RA patients and in RA SF (∼3%). In RA synovial tissue CD94/NKG2A was expressed by the majority of NK cells and a small subset of T cells. CD94/NKG2A+ cells were predominantly localized in lymphoid aggregates, but also present throughout RA synovium, whereas CD94/NKG2A+ cells were absent in synovium from HD. The CD94/NKG2A+ ligand, HLA-E, was detected on all infiltrating leukocytes in RA SF and synovium, at levels at least comparable to PB leucocytes from HD. Moreover, HLA-E was expressed by resident cells such as synoviocytes and endothelial cells in RA synovium.

Conclusions These data demonstrate that CD94/NKG2A and its ligand HLA-E are expressed at sites of inflammation in RA. NNC141-0100 specifically binds to CD94/NKG2A+ NK cells accumulating in inflamed joints of RA patients, thus treatment with NNC141-0100 may promote the elimination of activated pro-inflammatory cells and suppress inflammation in RA patients. NNC141-0100 is currently being developed for the treatment of RA.

  1. Teixeira de Matos C et al. Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion. Immunology 2007; 122 (2):291-301

  2. Leavenworth JW et al. Mobilization of natural killer cells inhibits development of collagen-induced arthritis. Proc Natl Acad Sci USA 2011; 108 (35):14584-14589

Disclosure of Interest V. Pascal Shareholder of: Novo Nordisk A/S, Employee of: Novo Nordisk A/S, Y. Sundström Grant/Research support from: Novo Nordisk A/S, A. Fasth Grant/Research support from: Novo Nordisk A/S, V. Malmström Grant/Research support from: Novo Nordisk A/S, L. Berg Grant/Research support from: Novo Nordisk A/S, P. Kvist Shareholder of: Novo Nordisk A/S, Employee of: Novo Nordisk A/S, P. Spee Shareholder of: Novo Nordisk A/S, Employee of: Novo Nordisk A/S, E. Galsgaard Shareholder of: Novo Nordisk A/S, Employee of: Novo Nordisk A/S

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