“Development of humanized blocking monoclonal antibodies against IL-3 for treatment of patients with rheumatoid arthritis”
We have shown recently that basophils importantly contribute to humoral memory immune responses. After primary immunization basophils capture antigen-specific immunoglobulins and are activated immediately after re-exposure to the antigen in vitro and in vivo. Thereby basophils are the almost exclusive and most important source of IL-6 and IL-4 during antigen restimulation and markedly enhance the activation, proliferation and plasma cell differentiation of B cells. We have also shown that basophils are present in inflamed joints of mice with collagen induced arthritis in much higher numbers than mast cells and that artificial activation of basophils (e.g. with antibodies against IgE) during the course of the disease result in a marked exacerbation of arthritis and increased antibody titers against collagen. Moreover, we found increased levels of IL-3 in the joints of mice during the early phase of arthritis. Even minimal concentrations of IL-3 result in a pronounced activation and a markedly prolonged survival of basophiles.
These results prompted us to analyze the role of IL-3 in collagen induced arthritis. Application of IL-3 during the progression phase of arthritis markedly aggravated the disease while blockade of IL-3 with a monoclonal antibody markedly reduced the progression of arthritis. Based on the fact that IL-3 deficient mice are healthy (in contrast to mice that lack TNF-alpha or B cells, two widely used therapies for rheumatoid arthritis in humans), we propose that blockade of IL-3 will be an effective therapy of rheumatoid arthritis with a favourable safety profile compared to currently available drugs.
We therefore propose to generate high affinity blocking antibodies against human IL-3. These antibodies will be characterized in vitro in terms of inhibition of IL-3 induced activation of basophils and in further functional assays. In addition, crossreactivity of the IL-3 antibodies with IL-3 from rats or non-human primates will be tested, to perform studies concerning safety, tolerability, pharmacokinetics and efficacy in a suitable animal model. The best antibody candidate will be selected for humanization. To be able to achieve this goal within the time period and budget of the BayImmuNet project we plan to perform humanization together with the MRC-Technology (London), where we already have established a collaboration concerning humanization of a different antibody.