NKG2A / NNC141-0100 at the EULAR 2012

NNC141-0100 is a humanized anti-human NKG2A monoclonal antibody that blocks interaction between CD94/NKG2A. If you are look for the study " Safety and Tolerability of NNC0141-0000-0100 in Subjects With Rheumatoid Arthritis", I must disappoint you as this phase 1 study is still recruiting and my guess is that some data will be presented at the ACR meeting 2012 in Washington. At the EULAR meeting 2012 in Berlin we were shown in vitro studies.

I will show you the conclusions, but it comes to the point that CD94/NKG2A is expressed at sites of inflammation in rheumatoid arthritis and is targeted by NNC141-0100.

Let´s go into detail. V. Pascal and colleagues looked into the binding specificity of NNC141-0100 to CD94/NKG2A receptors in peripheral blood, synovial fluid and/or synovial tissue from RA patients and healthy donors; and more, but here I won´t get into detail. The authors come to the conclusion that NNC141-0100 may promote the elimination of activated pro-inflammatory cells and suppress inflammation in rheumatoid arthritis patients.

[AB0071] CHARACTERIZATION OF NNC141-0100, A THERAPEUTIC ANTIBODY TARGETING INHIBITORY CD94/NKG2A RECEPTORS EXPRESSED IN INFLAMED JOINTS OF RHEUMATOID ARTHRITIS PATIENTS
V. Pascal1, Y. Sundström2, A. Fasth2, V. Malmström2, L. Berg2, P.H. Kvist3, P. Spee1, E.D. Galsgaard3. 1Department of Translational Immunology, Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark; 2Department of Medicine, Unit of Rheumatology, Karolinska University Hospital, Stockholm, Sweden; 3Department of Histology, Biopharmaceutical Research Unit, Novo Nordisk A/S, Maaloev, Denmark
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.

The study of N. Nielsen and colleagues show that natural killer cells may play a role in the elimination of fibroblast-like synoviocytes and may be blocked via CD94/NKG2A with NNC141-0100.

[FRI0020] BLOCKING THE INHIBITORY CD94/NKG2A NK CELL RECEPTOR WITH A NOVEL ANTI-NKG2A MAB ENHANCES THE SUSCEPTIBILITY OF RHEUMATOID ARTHRITIS FIBROBLAST-LIKE SYNOVIOCYTES (FLS) TO NK CELL-MEDIATED CYTOTOXICITY
N. Nielsen1, E.D. Galsgaard2, D. Ahern3, M. Andersen1, P. Spee1, M. Feldmann3, F. Brennan3, K. Söderström1. 1Department of Translational Immunology, Biopharmaceutical Research Unit; 2Department of Histology, Biopharmaceutical Research Unit, Novo Nordisk, Maaloev, Denmark; 3Kennedy Institute of Rheumatology, University of Oxford, London, United Kingdom
Conclusions: This study is the first to suggest that NK cells may play a role in the elimination of FLS, a process that is enhanced upon blocking the ability of HLA-E to engage the inhibitory CD94/NKG2A NK cell receptor. Exploitation of the cytotoxic potential of NK cells by blocking CD94/NKG2A with the novel humanized anti-NKG2A mAb NNC141-0100 may thus yield an opportunity for therapeutic treatment of chronic inflammation. NNC141-0100 is currently being tested in a phase I clinical trial for rheumatoid arthritis.


K. Söderström and colleagues could show that NNC141-0100 "leads to suppression of osteoclast formation and subsequent bone erosion, as well as a reduction in IL-6 levels in vitro."

[OP0142] MASKING CD94/NKG2A USING A NOVEL THERAPEUTIC MAB RESULTS IN SIGNIFICANT SUPPRESSION OF IL-6 LEVELS AND REDUCED OSTEOCLAST FORMATION IN RHEUMATOID ARTHRITIS EX VIVO CULTURES
K. Söderström1, Y. Sundström2, L. Berg2, D. Schepis2, E.D. Galsgaard3, L. Klareskog2, N. Wagtmann1. 1Department of Translational Immunology, Novo Nordisk A/S, Måløv, Denmark; 2Department of Medicine, Unit of Rheumatology, Karolinska Institutet, Stockholm, Sweden; 3Department of Histology, Novo Nordisk A/S, Måløv, Denmark
Conclusions: This study shows that blocking CD94/NKG2A with anti-NKG2A mAb NNC141-0100 that is currently being developed for the treatment of RA, leads to suppression of osteoclast formation and subsequent bone erosion, as well as a reduction in IL-6 levels in vitro. Based on these findings, we propose that anti-NKG2A therapy may have a beneficial effect in vivo in RA patients.

L. Alifrangis and colleagues looked at affinity and potency of NNC141-0100 and it´s implications for dosing in the first-in-man trial in rheumatoid arthritis, which looks good to get started.

[THU0110] AFFINITY AND POTENCY OF THE ANTI-NKG2A MAB NNC141-0100: IMPLICATIONS FOR MABEL AND DOSING IN THE FIRST-IN-MAN TRIAL IN RHEUMATOID ARTHRITIS
L. Alifrangis1, P. André2, V. Pascal3, E. Bonnet2, L. Radzikowski4, M.B. Petersen1, M. Bléry2. 1Non-Clinical Development, Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark; 2Innate Pharma, Marseille, France; 3Translational Immunology, Biopharmaceutical Research Unit; 4Dev. Bioanalysis, Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark
Conclusions: Given the observed difference between affinity and potency, the MABEL dose for the First-In-Man trial in RA patients had a high predicted CD94/NKG2A receptor occupancy of 90%, while the expected cytotoxicity as measured by the degranulation marker CD107 was much lower (<1%).


The in vitro studies look good, now we´re eager to now if the concept proofs to be working in vivo. It would mean a novel approach to treat rheumatoid arthritis.

NNC141-0100 - please give the baby a name!