Specific targeting of a pro-inflammatory B cell subset in rheumatoid arthritis.

In autoimmune diseases the immune system, which should defend us against infection, mistakes some of our body's tissues as a threat. It responds to this mistaken threat by attacking the tissue in question with the multiple types of leucocytes (white blood cells) that it has at its disposal. B cells are a particular type of leucocyte that has been shown to pay an important role in the ongoing disease processes faced by patients with rheumatoid arthritis (RA). This is highlighted by how well RA symptoms respond to B cell-depleting therapy (BCDT) using rituximab, an antibody drug which removes the vast majority of B cells. However, not all B cells are involved the pathology of RA and most are actually helpful and enable us to respond to infection and vaccination. The major disadvantage of BCDT is that it indiscriminately removes most B cells without specifically targeting those that are involved in pathology. In the long term, this puts patients at risk of infection, especially elderly patients, who often have difficulties defending themselves against viruses and bacteria already. Also, for several months after the treatment the patients will not respond efficiently to vaccination. In our work, we have identified a subtype of B cells, which is present in the inflamed joints of patients with RA and produces factors that activate inflammation and joint destruction. They do this by producing two small proteins, TNF and RANKL, which activate other cells to invade the joint and to destroy bone structure. We have also found that some these cells are specifically involved in the autoimmune process, and may be part of the process that starts off the disease. In our most recent work, we have identified a marker protein that is found only on this type of cells. It is called FcRL4. We now plan to develop a new drug, which like rituximab is an antibody that specifically targets FcRL4+ B cells. With this drug we hope to remove just the B cells that are aggressive in disease while the rest of the B cells will be maintained and will be available to defend us against infection. We plan to do this by having a range of different antibodies specific for FcRL4 produced and will then will run a series of experiments to test firstly whether these antibodies can be used to remove FcRL4+ B cells and then secondly choose the best antibodies to test whether removing FcRL4+B cells from samples of patient synovium will effectively reduce inflammation. This work will be done by a dedicated team of medical doctors, scientists and nurses who work together in a new institute built into the New Queen Elizabeth Hospital. We endeavor to involve the patients into our research to help us to understand this devastating disease better and to develop new and safe therapies.

The importance of B cells in the pathophysiology of rheumatoid arthritis is highlighted by the clinical effectiveness of B cell-depleting therapy (BCDT) using rituximab, an anti CD20 antibody(1). Potential mechanisms by which B cells may drive disease processes in RA include their ability to produce autoantibody, act as antigen-presenting cells, or secrete cytokines. The best characterized autoantigens in RA are posttranslationally citrullinated proteins. The major disadvantage of currently available BCDT is that it indiscriminately removes the vast majority of B cells without specifically targeting those that are involved in pathology.
In a systematic study of synovial cytokine expression we have identified a pro-inflammatory B cell population that expresses high levels of RANKL and TNF at the site of inflammation, in the synovial fluid and tissue of patients with RA (2, 3). In an extensive study of the immunophenotype of these cells we have established that they are characterized by surface expression of FcRL4, a transmembrane protein that is related to Fc receptors (3). FcRL4+ B cells express high levels of the costimulatory molecules CD80 and CD86 (3, 4). Expression of FcRL4 is highly restricted to this B cell subset and FcRL4 mRNA expression was detected in inflamed but not in uninflamed synovium. Due to their expression of pro-inflammatory cytokines, their capacity for costimulation and their recognition of citrullinated autoantigens we propose that FcRL4+ B cells are a promising clinical target. We plan to use a custom service offered by AbD Serotec under license from Morphosys to generate human antibodies and use them to target FcRL4+ inflammatory B cells in vitro and in mouse/human chimeric models. Starting with a range of antibodies, we will select the most promising clones over a series of in vitro and in vivo experiments. These experiments will provide data that will allow us to assess the potential of FcRL4 as a target for a novel therapy for RA.

Patients:
In England some 580,000 adults have RA, with around 26,000 new diagnoses each year. B cell depleting therapy (BCDT), is currently the preferred treatment for RA patients failing TNF blocking therapy. As around 50% of patients treated with TNF blockade show an unsatisfactory response, BCDT is used in a considerable number of patients. BCDT is effective, but has the disadvantage that it impairs the patient's ability to respond to vaccination and to infection with newly encountered pathogens. Patients with RA are already at a more than twofold higher risk of infection when compared to the general public.The safer therapy we are aiming to develop would impact on patient's quality of life and their ability to stay in the workforce by reducing their risk of infections.

Industry: Our aims are aligned with industry needs in terms of identification and exploitation of novel therapeutic targets. It also maps onto government's strategy for life sciences aiming to make the UK a world-leading place for life sciences investment: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/32457/11-1429-strategy-for-uk-life-sciences.pdf
The Rheumatology Research Group at Birmingham is an active participant and one of nine Centres involved in the NIHR TRP initiative supporting joint-related inflammatory disease, and we expect this to facilitate interaction with industry through the NIHR Office for Clinical Research Infrastructure (NOCRI). To-date, there are 12 ongoing interactions with industry, all at varying stages of development.

Economic impacts: The National Audit Office (NAO; 2009) has estimated that RA costs the NHS around £560 million a year and that the additional cost to the economy of sick leave and work-related disability is £1.8 billion a year. Development and delivery of a novel therapy that is, importantly, more safe than existing strategies for the targeting of B cells would bring economic and industrial growth both through revenues generated by the drug and by reduction of costs and loss of revenue due to infections. Enhanced UK competitiveness and prosperity would result through international commercialisation and exploitation alongside the planned programme to build the UK's capacity and research strength to tackle a chronic disease that is a heavy burden to the NHS.

Voluntary sector: This study will deliver enhanced returns on, and enhanced collaboration within existing Arthritis Research UK investment in Birmingham. This includes the Centre of Excellence in the pathology of RA, and delivering synergy with the Birmingham Experimental Arthritis Treatment Centre - one of seven linked units designed to enhance early phase trial infrastructure for initiatives including the Translational Research Partnerships.

The General Public: Through public engagement, including the voluntary sector, we will continue to deliver information about the progress of our study.

Academia: The identification of FcRL4 B cells in the rheumatoid synovium has already raised significant interest in the field. We will continue to report our advances, not only in the context of target development but also in the new understanding of disease processes generated by our studies. Researchers working on other inflammatory diseases will benefit from discovery
of a newly identified and validated clinical target and the associated shift in our understanding of mechanisms of chronic inflammation.