Improving Health by Investing in Medical Education

The antibody-mediated targeted delivery of cytokines to sites of disease is a promising avenue for cancer therapy, but it is largely unexplored for the treatment of chronic inflammatory conditions. Using both radioactive and fluorescent techniques, the human monoclonal antibodies L19 and G11 (specific to two markers of angiogenesis that are virtually undetectable in normal adult tissues) were found to selectively localize at arthritic sites in the murine collagen-induced model of rheumatoid arthritis following intravenous (i.v.) administration. The same animal model was used to study the therapeutic action of the L19 antibody fused to the cytokines IL-2, tumour necrosis factor (TNF) and IL-10. Whereas L19–IL-2 and L19–TNF treatment led to increased arthritic scores and paw swellings, the fusion protein L19–IL-10 displayed a therapeutic activity, which was superior to the activity of IL-10 fused to an antibody of irrelevant specificity in the mouse. The anti-inflammatory cytokine IL-10 has been investigated for the treatment of patients with rheumatoid arthritis, but clinical development plans have been discontinued because of a lack of efficacy. Because the antigen recognised by L19 is strongly expressed at sites of arthritis in humans and identical in both mice and humans, it suggests that the fusion protein L19–IL-10 might help overcome some of the clinical limitations of IL-10 and provide a therapeutic benefit to patients with chronic inflammatory disorders, including arthritis. Introduction The therapeutic potential of recombinant cytokines is often limited by severe toxicities, even at low doses, thus preventing dose escalation and the establishment of a sufficient concentration at target tissues. In principle, monoclonal antibodies could be used to deliver cytokines to sites of disease, thus increasing their potency and sparing normal tissues. Indeed, several antibody–cytokine fusion proteins have been investigated for cancer therapy applications, often with impressive therapeutic results [1-4]. Components of the modified extracellular matrix (ECM) are particularly attractive for antibody-based targeting applications, because these antigens are often stable and abundant [5]. In the past, our group has focused its efforts on the development of human monoclonal antibodies, which recognise ECM components that are virtually absent in normal tissues but strongly expressed at sites of disease and have a prominent perivascular pattern of expression [6]. Splice isoforms of abundant ECM components seem to be particularly suited for antibody-mediated in vivo targeting applications. For example, the extra domai [7-10] and C domain of tenascin-C [11-13] are two of the most promising markers of angiogenesis, which can be targeted using the high-affinity monoclonal antibodies L19 and G11, respectively [14-19]. Several derivatives of the L19 antibody have exhibited impressive therapeutic activity in animal models of cancer [1,2,4,20-24] and angiogenesisrelated ocular disorders [25]. In particular, the antibody–