Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating Phase I, Healthy Subjects Study of Intravenous OPN-305, a Humanized Anti-TLR2 Antibody

OPN-305 is a humanized IgG4 monoclonal antibody against Toll-like receptor (TLR)2 being developed by Opsona Therapeutics. It is believed to function by targeting the ligand-binding site on the TLR2 receptor, thereby preventing heterodimerization of the receptor with TLR1 or TLR6. OPN-305 antagonizes TLR2-dependent cytokine production.1 OPN-305 contains a mutation in the hinge region that prevents Fab arm switching in vivo; the molecule is stable and retains its monospecificity for TLR2. Rather than using traditional complimentarity determining region grafting, OPN-305 was generated using a proprietary method of humanization known as “Composite Antibody Technology,” developed by Antitope (Cambridge, UK). Using this method, composite variable region sequences guided by the reference antibody, OPN-301, contained in human antibody sequence data banks were sourced to form V-region sequences composing fully human sequences. These segments were then modeled in silico to identify constraining sequences within the murine parent sequences. Finally, candidate sequences were screened in silico for potential human leukocyte antigen–binding sites, and any resulting T-cell epitopes identified were removed. The initial target indication for OPN-305 is delayed graft function (DGF). This is the most common complication in the immediate post-transplantation period, affecting 25–35% of all patients who receive a cadaveric donor graft.2,3 The upregulation of TLR2 and its ligation by either exogenous or endogenous danger signals has been demonstrated to play a critical role in the inflammatory cascade that exacerbates tissue damage after reperfusion.4 TLR2 mRNA is constitutively expressed by tubular epithelial cells in the murine kidney and increases following ischemia, driving a TLR2-mediated increase in cytokines.5,6,7 Putative endogenous ligands for TLR2, such as heat shock proteins and necrotic cells, also increase following ischemic injury.1,8,9,10 The extravasation of immune cells and secretion of proinflammatory cytokines after reperfusion of transplanted organs are well characterized and are believed to exacerbate DGF and organ rejection. OPN-305 specifically targets and blocks TLR2 with the aim of preventing DGF by minimizing the sequelae of ischemia/reperfusion injury by tempering the innate immune response following reperfusion. Given the high degree of conservation of TLR2 sequence homology across species (e.g., human and cynomolgus monkey TLR2 share absolute identity of 96.18%), OPN-305 and OPN-301, the murine monoclonal parent antibody from which it is derived, have been effective in a number of animal models including ischemia/reperfusion injury in mice1 and pigs.11 In addition, in vitro data indicate that OPN-305 antagonizes TLR2 signaling in mice,1 pigs,11 cynomolgus monkeys, and human cells (see Supplementary Data and Supplementary Figure S1 online). These data, together with data from the toxicology studies performed in mice, monkeys, and the first-in-human phase I study, support the starting dose of OPN-305 for clinical development. The aim of this first-in-human phase I study was to provide an initial assessment of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of OPN-305 after infusing single ascending i.v. doses in healthy adult subjects. The study characterized the various doses and infusion times in healthy subjects as a prelude to initiating trials in patients.