Institute of Bone and Joint Surgery

The antibody-mediated targeted delivery of cytokines to sites of disease is a promising avenue for the therapy of cancer, but 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 which 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 administration. The same animal model was used to study the therapeutic action of the L19 antibody fused to the cytokines IL2, TNF and IL10. While L19-IL2 and L19-TNF treatment led to increase arthritic scores and paw swellings, the fusion protein L19-IL10 displayed a therapeutic activity, which was superior to the one of IL10 fused to an antibody of irrelevant specificity in the mouse. The anti-inflammatory cytokine IL10 has been investigated for the treatment of patients with rheumatoid arthritis, but clinical development plans have been discontinued, due to lack of efficacy. The fact that the antigen recognized by L19 is strongly expressed at sites of arthritis in humans, and is identical in mouse and man, suggests that the fusion protein L19-IL10 may help overcome some of the clinical limitations of IL10 and may provide a therapeutic benefit to patients with chronic inflammatory disorders, including arthritis.