AB0451 NI-0101, a Monoclonal Antibody Targeting Toll Like Receptor 4 (TLR4) Being Developed for Rheumatoid Arthritis (RA) Treatment with a Potential for Personalized Medicine. (9th June 2015)

• Record Type: Journal Article
• Authors: Monnet, E.; Shang, L.; Lapeyre, G.; deGraaf, K.; Hatterer, E.; Buatois, V.; Elson, G.; Ferlin, W.; Gabay, C.; Sokolove, J.; Jones, S.A.; Choy, E.H.; McInnes, I.B.; Kosco-Vilbois, M.; de Min, C.
• Is Part Of: Annals of the rheumatic diseases. Volume 74(2015)Supplement 2
• Page Start: 1046
• Page End: 1046
• Publication Date: 2015-06-09
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2015-eular.3801
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Innate immunity is implicated in RA pathogenesis and is likely initiated via TLR pathways. NI-0101 is the first humanized monoclonal antibody (mAb) that blocks TLR4 signaling independently of ligand type (i.e., exogenous/endogenous) and concentration. Objectives: To determine preliminary tolerability, safety, pharmacokinetic (PK)/pharmacodynamic (PD) profiles after single administrations of different NI-0101 doses to healthy volunteers (HV), as well as to investigate NI-0101 ability to block TLR4-mediated inflammatory cytokine production induced by endogenous TLR4 ligands. Methods: A PK/PD guided single ascending dose Phase 1 study was conducted in 73 HV, in the presence of in vivo and ex vivo challenges with the exogenous TLR4 ligand, lipopolysaccharide (LPS). In parallel, monocytes obtained from RA patients were stimulated with endogenous TLR4 ligands or synovial fluids (SF) of RA patients in presence and absence of NI-0101. The correlation of TLR4 blockade with level of endogenous TLR4 ligands in SF was assessed. Finally, the anti-mouse TLR4 surrogate mAb, 5E3, was tested in murine models of RA (IL-1Rn -/- mice and collagen induced arthritis). Results: NI-0101 was administered up to a single dose of 15 mg/kg in the Phase 1 study in HV and showed no safety concerns. The predictable PK profile was biphasic, similar to other therapeutic IgG targeting cell surface receptors. NI-0101 administration inhibited ex vivo and in vivo LPS-induced cytokine release (complete inhibition from a dose of 1 mg/kg), as well as prevented CRP increase and the occurrence of flu-like symptoms following LPS administration to HV. NI-0101 PK/PD profiles allowed, through modeling and simulation of multiple administration of NI-0101, to identify an appropriate dose range to be tested in Phase 2. NI-0101 interaction with TLR4 and Fcγ Receptor, in vitro, efficiently blocked TLR4 activation by citrullinated protein immune complexes (cP-IC) present in SF of RA patient sub-populations. NI-0101 blocked the activation of monocytes stimulated with SF from RA patients. This inhibition correlated with the presence of endogenous TLR4 ligands in the synovial fluids (e.g., anti citrullinated protein antibodies, citrullinated fibrinogen immune complex). Therapeutic administration of 5E3 ameliorated disease progression in both mouse models of arthritis. Conclusions: NI-0101 blocks TLR4 activation induced by in vivo LPS challenges in HV and by cP-IC in RA patient cells. Taken together, these data strongly support the potential of TLR4 as a valid therapeutic target in RA, and provide an opportunity to evaluate specific endogenous TLR4 ligands as biomarkers of treatment response in Phase 2. Disclosure of Interest: E. Monnet Employee of: Novimmune, L. Shang Employee of: Novimmune, G. Lapeyre Employee of: Novimmune, K. deGraaf Employee of: Novimmune, E. Hatterer Employee of: Novimmune, V. Buatois Employee of: Novimmune, G. Elson Employee of: Novimmune, W. Ferlin Employee of: Novimmune, C. Gabay Consultant for: Novimmune, J. Sokolove Consultant for: Novimmune, S. Jones Consultant for: Novimmune, E. Choy Consultant for: Novimmune, I. McInnes Consultant for: Novimmune, M. Kosco-Vilbois Employee of: Novimmune, C. de Min Employee of: Novimmune