Evidence of NI‐0101 pharmacological activity, an anti‐TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS

Abstract

Toll-like receptor-4 (TLR4) pathways are major contributors to pathological inflammatory responses induced by tissue damage. NI-0101 is the first monoclonal antibody (mAb) blocking TLR4 signaling. This activity is independent of the ligand type and concentration, therefore, potentially blocking any TLR4 ligands. A phase I single ascending dose study was conducted in 73 healthy volunteers to evaluate NI-0101 tolerability, preliminary safety, pharmacokinetics (PKs), and pharmacodynamics (PDs), in absence and in presence of a systemic challenge with lipopolysaccharide (LPS), a TLR4 ligand. NI-0101 was well tolerated without safety concern. The PK profile was characterized by a half-life of ∼10 days at high concentrations and by a rapid elimination at low concentrations due to expected target-mediated drug disposition. NI-0101 prevented cytokine release following ex vivo and in vivo LPS administration and prevented the C-reactive protein (CRP) increase and the occurrence of flu-like symptoms expected following the in vivo administration of LPS.

Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics

“…It can potently inhibit TLR4 signaling by blocking TLR4 dimerization, which is independent on the ligand type and concentration (Monnet et al, 2015). NI-0101 just completed a phase I clinical trial (NCT01808469) and the results were very encouraging (Monnet et al, 2017). NI-0101 was well-tolerated without safety concerns at various doses; it could successfully block cytokine release ex vivo and in vivo , and prevent flu-like symptoms upon LPS administration.…”

TLRs in pulmonary diseases

“…It has the potency to reduce cytokine secretion and averts flu and its symptoms in ex vivo and in vivo models. This drug has successfully completed phase I clinical trial and is proven to be a safe and non-toxic drug at various concentrations [263]. 1A6, another anti-TLR4 monoclonal antibody is effective in reducing inflammatory disorders and has positive role in lung injury models [264].…”

Disaccharide‐Based Anionic Amphiphiles as Potent Inhibitors of Lipopolysaccharide‐Induced Inflammation

“…Solvents were removed under reduced pressure at 40 8C. NMR spectra were recorded at 298 K on aB ruker Avance III 600 spectrometer ( 1 Ha t6 00.22 MHz; 13 Ca t 150.92 MHz; 31 Pa t2 42.97 MHz). Chemical shifts are reported in ppm (the bGlcN NMR signals are indicated by primes); 1 HNMR spectra in CDCl 3 are referenced to internal TMS and 13 CNMR spectra are referenced to the corresponding solvent signal (77.0 ppm for CDCl 3 ).…”

“…Chemical shifts are reported in ppm (the bGlcN NMR signals are indicated by primes); 1 HNMR spectra in CDCl 3 are referenced to internal TMS and 13 CNMR spectra are referenced to the corresponding solvent signal (77.0 ppm for CDCl 3 ). 31 PNMR spectra are externally referenced to PPh 3 (À6.00 ppm in CDCl 3 ). High-resolution mass spectrometry (HRMS) was carried out from 1-10 mg L À1 acetonitrile solutions via LC-TOF MS (Agilent 1200SL HPLC and Agilent 6210 ESI-TOF,A gilent Te ch-nologies) using CeQuant ZIC-HILIC 3.5 mm, 100 column and elution with linear gradient (0.5 mL min À1 )o f0 .1 %a queous HCOOH (5 %t o6 0%)i nC H 3 CN cont.…”

“…[14,15] It was unequivocally shown that down-regulation of TLR4-mediated signaling is beneficial for treatment of chronic and acute inflammation-related conditions including arthritis, [16] asthma, [17] neuroinflammation, [18] viral respiratory infection, [19] influenza [20] and sepsis [12,15,[21][22][23] Quite av arietyo fd ifferent tactics have been suggested for the inhibition of the deleteriousi nnate immune responses induced by LPS, which include deactivation of LPS by cationic antimicrobialp eptides; [24][25][26] intervention with the LPS transfer cascade involving LBP (LPS-binding protein) and CD14 (cluster of differentiation 14) [27][28][29][30] including development of TLR4 neutralizing antibodies. [31,32] Several innovative molecules with no similarity to Lipid Ah ave been proposed as candidates for blocking LPStriggered pro-inflammatory signaling. [33][34][35] Still, no universal therapeutic remedy has been developed so far,a nd sepsis remains the leading causeo fd eath in intensive care units with up to 50 %m ortality rate.…”