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