PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases

Abstract

The proinflammatory cytokine, tumour necrosis factor (TNF ) has been shown to play a pivotal part in mediating acute and chronic inflammation. The activities of TNF are modulated by the proteolytic shedding of the soluble extracellular domains of the two TNF receptors, p55 sTNF-RI and p75 sTNF-RII. Amgen Inc has cloned and expressed a recombinant form of a natural inhibitor of TNF , referred to as recombinant human soluble TNF receptor type I (r-Hu-sTNF-RI, sTNF-RI). sTNF-RI is an E coli recombinant, monomeric form of the soluble TNF-type I receptor. A high molecular weight polyethylene glycol (PEG) molecule is attached at the N-terminus position to form the molecule intended for clinical evaluations (PEG sTNF-RI). Preclinical studies to date demonstrate that PEG sTNF-RI is eYcacious in rodent models of chronic inflammatory disease including rheumatoid arthritis and Crohn's disease at doses as low as 0.3 mg/kg given every other day. This dose results in plasma concentrations of 0.3 to 0.5 µg/ml. Higher doses with correspondingly higher plasma concentrations yield higher eYcacy. It has also demonstrated eYcacy in E coli lipopolysaccharide, and Staphylococcus enterotoxin B mediated models of acute inflammation in rodents and primates. Pharmacokinetic studies in mice, rats, cynomolgus monkeys, baboons, and chimpanzees have been conducted with PEG sTNF-RI. Absorption from a subcutaneous dose was slow, with the time to reach maximal plasma concentrations of 24-48 hours in rats, and in monkeys, and 3-29 hours in chimpanzees. The initial volume of distribution of PEG sTNF-RI was essentially equivalent to that of plasma (40 ml/kg). This suggests the protein does not appear to extensively distribute from the systemic circulation with a volume of distribution at steady state (Vss) less than 200 ml/kg in all species studied. These results are consistent with previous experience with PEGylated proteins in which PEGylation decreases both the rate of absorption and the plasma clearance of human recombinant proteins in animals and humans. The use of a PEG molecule will probably provide a more advantageous dosing schedule (that is, less frequent dosing) for the patient compared with a non-PEG sTNF-RI.

Spinal Glia and Proinflammatory Cytokines Mediate Mirror-Image Neuropathic Pain in Rats

“…4 A). Pretreatment with intrathecal TNFbp prevented these SIN-induced pain changes through 24 hr, in keeping with the prolonged half-life of this compound relative to IL1ra (Bendele et al, 1998;Edwards, 1999) (Fig. 4 A, B).…”

Neutralization of Tumor Necrosis Factor-Alpha Reduces Renal Fibrosis and Hypertension in Rats with Renal Failure

“…This time point was chosen since the general health status of untreated animals with renal failure significantly dropped after 7–8 weeks experiencing weight loss, cerebrovascular lesions with paralysis or sudden death [28,30]. The dose of PEG-sTNFR1 was chosen based on preclinical studies showing that PEG-sTNFR1 administration every other day limits the inflammatory response to rheumatoid arthritis in the rat [29,31], and reduces renal inflammation and apoptosis in rats with unilateral ureteral obstruction [7,32]. At week 6 of treatment, the rats were placed in metabolic cages and a 24-hour urine sample was collected and stored at –20°C.…”

“…One week after the surgery, rats with reduced renal mass were divided into two groups with similar systolic blood pressure assessed by the tail-cuff method, which was documented to correlate with renal failure [16,23,28]. Renal failure rats received the long-acting TNF-α neutralization molecule PEG-sTNFR1, a soluble TNF type 1 receptor that the half-life is prolonged by pegylation [29] (1.25 mg/kg s.c., 3 times/week; Amgen Inc., Thousand Oaks, Calif., USA; n = 12) or the vehicle (n = 12) for 6 weeks. This time point was chosen since the general health status of untreated animals with renal failure significantly dropped after 7–8 weeks experiencing weight loss, cerebrovascular lesions with paralysis or sudden death [28,30].…”

Tumor Necrosis Factor (TNF) Protects Resistant C57BL/6 Mice against Herpes Simplex Virus-Induced Encephalitis Independently of Signaling via TNF Receptor 1 or 2

“…Mice were treated on days 0, 2, 4, 6, and 8 with 30 mg/kg PEGylated monomeric sTNFR1, which binds TNF but is not known to bind LT (22), 250 g hamster anti-mouse TNF (clone 5B8), which does not bind LT (Hiko Kohno, Amgen, personal communication), or a total dose of 22 g of a 27-mer siTNF (IDT, Coralville, IA). The siTNF was delivered as a complex with TransIT TKO (Mirus Bio, Madison, WI) to the peritoneal cavity as we have described previously (5), using six doses over 9 days (2 g on day 0 and 4 g each on days 1, 2, 4, 6, and 8).…”