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.
IMO-3100, a Toll-Like Receptor (TLR) Antagonist, Suppresses TLR7- and TLR9-Mediated Immune Responses in Non-Human Primates.
Bhagat2, Lakshmi, Tang2, Jimmy X., Sullivan2, Tim, Kandimalla1, Ekambar R., Agrawal2, Sudhir
Immune complexes containing host-derived nucleic acids have been shown to induce inflammatory responses mediated through TLR7 and TLR9 and manifest autoimmune diseases, such as lupus and psoriasis. Blocking TLR7- and TLR9-mediated immune responses through use of an antagonist represents a novel approach for the treatment of selected autoimmune diseases. IMO-3100 is a dual antagonist of TLR7 and TLR9, which has shown potent activity in preclinical disease models of lupus, collagen-induced arthritis, psoriasis, and hyperlipidemia. In the current study, we have evaluated IMO-3100 for its pharmacodynamic mechanism of action in non-human primates.
IMO-3100 was administered to cynomolgus monkeys (N=4) as a weekly dose of 1.5 mg/kg for 4 weeks. Blood samples were collected prior to and 72 hours after each IMO-3100 injection (i.e. Days 0, 3, 7, 10, 14, 17, 21, and 24) and also at days 28 and 35. PBMCs were isolated by Ficoll density gradient centrifugation method. PBMCs (1×106 cells/0.2 ml/well in 96 well plates) were incubated with agonists of TLR7 (50 mg/ml), TLR9 (3 mg/ml) or TLR4 (LPS, 100 ng/ml) for 24 hrs. Supernatants were harvested and IL-1b, IL-1Ra, IL-6, IL-8, IL-12, TNF-a, MIP-1a, MIP-1b, RANTES and MCP-1 levels in culture supernatants were determined using human cytokine antibody bead kits. IFN-a and IP-10 levels were measured by ELISA.
Weekly administration of IMO-3100 for 4 weeks resulted in 25 to 95% reduction in various cytokines and chemokines induced by TLR7 and TLR9 agonists, including IL-1b, IL-6, IL-12, IP-10, IFN-a, MIP-1a and MIP-1b, compared with pre-dose cytokine levels. The magnitude and duration of inhibition varied for different cytokines. Weekly administration of IMO-3100 led to continued suppression of cytokines at all time points up to day 28. By day 35, two weeks after the last dose of IMO-3100 administration, secretion of cytokines/chemokines rebounded or started to rebound to pre-dose levels. IMO-3100 showed insignificant suppression of TLR4 agonist (LPS)-induced cytokines in isolated PBMCs, suggesting specific inhibition of TLR7- and TLR9-mediated immune responses.
These results demonstrate that weekly administration of IMO-3100 to non-human primates suppresses ex-vivo immune responses mediated through TLR7 and TLR9, but not TLR4. IMO-3100 is in phase 1 clinical evaluation for potential applications in autoimmune and inflammatory diseases.
To cite this abstract, please use the following information:
Bhagat, Lakshmi, Tang, Jimmy X., Sullivan, Tim, Kandimalla, Ekambar R., Agrawal, Sudhir; IMO-3100, a Toll-Like Receptor (TLR) Antagonist, Suppresses TLR7- and TLR9-Mediated Immune Responses in Non-Human Primates. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :856