Antibody-based delivery of IL4 to the neovasculature cures mice with arthritis

Abstract

Antibody-cytokine fusion proteins (immunocytokines) are innovative biopharmaceutical agents, which are being considered for the therapy of cancer and chronic inflammatory conditions. Immunomodulatory fusion proteins capable of selective localization at the sites of rheumatoid arthritis (RA) are of particular interest, as they may increase the therapeutic index of the cytokine payload. The F8 antibody recognizes the alternatively spliced extra domain A of fibronectin, a marker of angiogenesis, which is strongly overexpressed at sites of arthritis. In this study, we investigated the targeting and therapeutic activity of the immunocytokine F8-IL4 in the mouse model of collagen-induced arthritis. Different combination regimes were tested and evaluated by the analysis of serum and tissue cytokine levels. We show that F8-IL4 selectively localizes to neovascular structures at sites of rheumatoid arthritis in the mouse, leading to high local concentrations of IL4. When used in combination with dexamethasone, F8-IL4 was able to cure mice with established collagen-induced arthritis. Response to treatment was associated with an elevation of IL13 levels and decreased IL6 plasma concentrations. A fully human version of F8-IL4 is currently being developed for clinical investigations.

Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions

“…Administration of L19-IL10 or F8-IL10 significantly lowered the arthritic score and led to reduced paw swelling compared with saline and the untargeted cytokine [62,65,66]. Moreover, combination of F8-IL10 with methotrexate or a murine analog of etanercept (TNFR2-Fc fusion) increased therapeutic activity in this setting [66,67]. Additionally, F8-IL10 significantly reduced lesion size in a mouse model of endometriosis [61].…”

“…An IL4 fusion to the F8 antibody in the diabody format [F8-IL4 (tetravil)] exhibited high therapeutic efficacy in mouse models of endometriosis, psoriasis and rheumatoid arthritis. Importantly, complete cures in a mouse model of rheumatoid arthritis were achieved when F8-IL4 was administered in combination with dexamethasone [67]. Moreover, F8-IL4 decreased ear swelling in imiquimod (IMQ)-induced and contact-hypersensitivity-induced mouse models of chronic skin inflammation.…”

“…In most cases, tumor-bearing animals are used for these studies, because it is easy to weigh neoplastic lesions and count radioactivity in those specimens. However, disease-homing properties in nononcological conditions can be adequately studied by noninvasive radioactive or fluorescent imaging techniques or by autoradiography [66,67]. Microscopic analysis of protein localization in tissue sections (e.g.…”

“…Pharmacodelivery applications for monoclonal antibodies, specific to the extra-domain A (EDA) of fibronectin, an antigen that is virtually undetectable in normal adult tissues [87]. Tissue stainings adapted, with permission, from [46,57,59,61,62,67]. …”

Progress and clinical potential of antibody-targeted therapy for arthritic damage

“…Mouse IL-4 (mIL-4) was fused to the F8 diabody [18] and shown to localize to inflamed CIA paws by autoradiography of radiolabeled immunocytokine. Moreover, this fusion protein decreased inflammation more than by control anti-HEL/mIL-4.…”