The potential therapeutic activity of a human monoclonal antibody to the human interleukin-12 p40 subunit (anti-IL-12p40) has been established both in vitro and in vivo, warranting a first-in-human investigation in psoriasis. This phase I, first-in-human, non-randomized, open-label study evaluated the short-term safety, pharmacokinetics, and clinical response of single, ascending, intravenous (IV) doses of anti-IL-12p40 in subjects with moderate-to-severe psoriasis vulgaris. Eighteen subjects with at least 3% body surface area involvement were enrolled in four dose groups (0.1, 0.3, 1.0, and 5.0 mg per kg). Safety, pharmacokinetics, and clinical response (e.g., Psoriasis Area and Severity Index (PASI)) were monitored at baseline and at specific time points over a 16-wk follow-up period. Anti-IL-12p40 was generally well tolerated. No related serious adverse events or infusion reactions were reported, and most adverse events were mild. IV anti-IL-12p40 yielded linear pharmacokinetics, with a mean terminal half-life of approximately 24 d. Dose-dependent associations with both the rate and extent of clinical response were observed across the four dose groups. Twelve of 18 subjects (67%) achieved at least a 75% improvement in PASI between 8 and 16 wk after study agent administration. Significant and sustained concentration-dependent improvements in psoriatic lesions were observed in most subjects.

Psoriasis is characterized by activation of T cells with a type 1 cytokine profile. IL-12 and IL-23 produced by APCs are essential for inducing Th1 effector cells. Promising clinical results of administration of an Ab specific for the p40 subunit of IL-12 and IL-23 (anti-IL-12p40) have been reported recently. This study evaluated histological changes and mRNA expression of relevant cytokines and chemokines in psoriatic skin lesions following a single administration of anti-IL-12p40, using immunohistochemistry and real-time RT-PCR. Expression levels of type 1 cytokine (IFN-γ) and chemokines (IL-8, IFN-γ-inducible protein-10, and MCP-1) were significantly reduced at 2 wk posttreatment. The rapid decrease of these expression levels preceded clinical response and histologic changes. Interestingly, the level of an anti-inflammatory cytokine, IL-10, was also significantly reduced. Significant reductions in TNF-α levels and infiltrating T cells were observed in high responders (improvement in clinical score, ≥75% at 16 wk), but not in low responders. Of importance, the levels of APC cytokines, IL-12p40 and IL-23p19, were significantly decreased in both responder populations, with larger decreases in high responders. In addition, baseline levels of TNF-α significantly correlated with the clinical improvement at 16 wk, suggesting that these levels may predict therapeutic responsiveness to anti-IL-12p40. Thus, in a human Th1-mediated disease, blockade of APC cytokines by anti-IL-12p40 down-regulates expression of type 1 cytokines and chemokines that are downstream of IL-12/IL-23, and also IL-12/IL-23 themselves, with a pattern indicative of coordinated deactivation of APCs and Th1 cells.

Background-Previous investigators have shown that systemic markers of inflammation may be increased in patients withacute ischemic syndromes or after percutaneous coronary revascularization and that persistent elevation in these markers is predictive of excess risk of subsequent adverse cardiac events. By virtue of its cross-reactivity with the glycoprotein IIb/IIIa, av␤3, and ␣M␤2 receptors, abciximab may reduce inflammatory processes. Methods and Results-Assays for the inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-␣ were performed on serum samples obtained from 160 patients in a placebo-controlled, randomized trial of abciximab during angioplasty. Eighty patients each had received a placebo or abciximab bolus plus a 12-hour infusion. Serum samples were drawn at baseline (before revascularization), 24 to 48 hours after study drug administration, and 4 weeks after study drug administration. Between baseline and 24 to 48 hours, the increase in C-reactive protein was 32% less in patients receiving abciximab than placebo (Pϭ0.025); the rise in interleukin-6 levels was 76% less in the abciximab group (PϽ0.001); and the rise in tumor necrosis factor-␣ levels was 100% less with abciximab therapy (Pϭ0.112). By 4 weeks, most marker levels had returned to baseline, with no significant differences between placebo and abciximab groups. Conclusions-Systemic markers of inflammation increase in the first 24 to 48 hours after angioplasty, but the magnitude of that rise is diminished by periprocedural abciximab. Some of the long-term clinical benefit derived from this agent may be related to an anti-inflammatory effect.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Interleukin (IL)‐6 is a cytokine known for pleiotropic and pro‐inflammatory functions. IL‐6 is involved in various disease processes including lupus erythematosus, rheumatoid arthritis, insulin resistance and malignancy. • Anti‐IL‐6 receptor therapy has recently been demonstrated to be effective in the treatment of patients with rheumatoid arthritis. WHAT THIS STUDY ADDS • Sirukumab, a human monoclonal antibody against soluble IL‐6, has been found to bind to human IL‐6 with high affinity and specificity and thus suppress the biological activity of IL‐6. Preclinical studies have demonstrated the safety of sirukumab in cynomolgus monkeys, a toxicologically relevant animal species, following repeated intravenous and subcutaneous administrations. • This study shows that sirukumab has desirable pharmacokinetic characteristics (linear pharmacokinetics with long half‐life), a low incidence of immunogenicity and a well‐tolerated safety profile in healthy subjects, supporting further development of sirukumab as a potentially valuable therapeutic agent. AIMS To assess the safety, tolerability, pharmacokinetics (PK) and immunogenicity of sirukumab (CNTO 136) following intravenous (i.v.) infusion in healthy subjects. METHODS Forty‐five healthy adult subjects (38 men and seven women) were randomly assigned to receive a single i.v. dose of placebo or sirukumab (0.3, 1, 3, 6 or 10 mg kg−1 in a dose‐escalating manner). All treated subjects were observed for 96 h post infusion and underwent 20‐week follow‐up evaluations. Serum samples were collected to measure sirukumab concentrations, pharmacodynamic biomarkers and antibodies to sirukumab. Non‐compartmental analysis and population PK modelling were conducted to characterize the PK of sirukumab. RESULTS Adverse events were generally brief in duration, mild or moderate in intensity and non‐dose‐dependent. No serious adverse events were observed in the sirukumab‐treated subjects. Both Cmax and AUC(0,∞) increased in an approximately dose‐proportional manner. Median terminal half‐life ranged from 18.5 to 29.6 days. A two‐compartment model adequately described the PK of sirukumab following i.v. administration. Population estimates for the clearance (CL), the central volume of distribution (V1), the inter‐compartmental clearance (Q) and the peripheral volume of distribution (V2) were 0.364 l day−1, 3.28 l, 0.588 l day−1 and 4.97 l, respectively. Compared with placebo subjects, a sustained decrease from baseline in C‐reactive protein was observed in all sirukumab‐treated dose groups, although no clear dose–response relationship was observed. No subjects were positive for antibodies to sirukumab. CONCLUSIONS Sirukumab had a well‐tolerated safety profile, desirable PK characteristics and a low incidence of immunogenicity following an i.v. infusion of 0.3 to 10 mg kg−1 in healthy subjects.

A single s.c. administration of IL-12/23 mAb was well tolerated and showed clinical response in subjects with moderate-to-severe psoriasis.