Method: The anti-human TLR4 mAb, NI-0101, was generated and shown to efficiently block TLR4 activation in vitro by exploiting a mechanism involving both Fv and Fc portions. Using exogenous, endogenous or chemical ligands, the capacity to block TLR4 activation was evaluated. Subsequently, NI-0101 was tested in synovial explant cultures obtained from RA patients. Furthermore, the corresponding mouse surrogate antibody was tested in a laboratory model of RA.
Result: Due to inhibition of TLR4 dimerization, NI-0101 efficiently blocked the activation of TLR4 by different ligands, including tenascin C, the endogenous ligand of TLR4 upregulated in synovial fluid from RA patients. Consistent with this result, NI-0101 reduced the spontaneous production of TNFα and IL-6 in synovial explant cultures from RA patients. To determine the effects of NI-0101 in vivo, we used the mouse surrogate antibody of NI-0101, 5E3. Therapeutic administration of 5E3 efficiently ameliorated disease progression in the he IL-1Rn-/- model of RA.
Conclusion: The therapeutic anti-human TLR4 mAb, NI-0101, has the capacity to interfere with not only LPS but also signaling of TLR4 through endogenous and chemical ligands. When used in in vitro models with tissue from RA patients, NI-0101 reduces spontaneous pro-inflammatory cytokine production. We demonstrated that anti-TLR4 mAb therapy is efficient in abolishing disease progression in arthritic mice. Taken together, these data promote NI-0101 as a promising treatment in RA. Moreover, by targeting a central upstream mediator in the inflammatory cascade, NI-0101 may have broad effects on RA pathogenesis and promote remission.
Disclosure: G. Elson, NovImmune S.A., 3 ; T. Page, None; V. Buatois, NovImmune S.A., 3 ; B. Daubeuf, NovImmune S.A., 3 ; L. Chatel, novimmune s.a., 3 ; L. Cons, NovImmune S.A., 3 ; C. Lippens, NovImmune S.A., 3 ; S. Salgado-Pires, NovImmune S.A., 3 ; W. Ferlin, NovImmune S.A., 3 ; M. Kosco-Vilbois, NovImmune S.A., 3 ; K. Midwood, None; L. Shang, NovImmune S.A., 3 .