Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNF alpha single-chain Fv antibody (ESBA105) designed for local therapeutic use

作者：Urech D M; Feige U; Ewert S; Schlosser V; Ottiger M; Polzer K; Schett G; Lichtlen P^*

来源：Annals of the Rheumatic Diseases, 2010, 69(2): 443-449.

DOI：10.1136/ard.2008.105775

Objectives: (1) To show that a single-chain Fv antibody (scFv) against tumour necrosis factor alpha (TNF alpha) (ESBA105) has efficacy comparable to a full length anti-TNF alpha IgG (infliximab); (2) to evaluate whether ESBA105 has all the properties required for the local treatment of arthritis; and (3) to investigate its discriminative tissue penetration properties.
Methods: In vivo efficacy was measured in arthritis of the knee joint induced by the intra-articular injection of recombinant human TNF alpha (rhTNF alpha) in Lewis rats. Cartilage penetration of scFv (ESBA105) and full length IgG (infliximab) were studied in bovine cartilage specimens ex vivo. Tissue penetration, biodistribution and pharmacokinetics of ESBA105 were followed and compared after intra-articular and intravenous administration.
Results: In cell culture, ESBA105 showed similar TNF alpha inhibitory potency to infliximab. In vivo, ESBA105 inhibited rhTNF alpha-induced synovial inflammation in rats with efficacy again comparable to infliximab. An 11-fold molar excess of ESBA105 over rhTNF alpha resulted in 90% inhibition of knee joint swelling, inflammatory infiltrates and proteoglycan loss from cartilage. In ex vivo studies of bovine cartilage, ESBA105 penetrated well into the cartilage whereas infliximab remained on the surface. In vivo, rapid penetration into the synovial tissue, cartilage and surrounding tissues was observed following intra-articular injection of [I-125]-ESBA105 into the knee joint of rabbits.
Conclusions: ESBA105 potently inhibits inflammation and prevents cartilage damage triggered by TNF alpha. In contrast to a full length IgG, ESBA105 also penetrates into cartilage and can be expected to reverse the TNF alpha-induced catabolic state of articular cartilage in arthritides.

• 出版日期2010-2