Dissecting the regulation of antibody immunotherapy by Fc gamma receptor IIB

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Biological therapies are one of the fastest growing sectors of the pharmaceutical industry, driven in large part by the success of monoclonal antibodies (mAbs). Since the approval of rituximab in 1997, mAbs are now successfully employed in the treatment of multiple diseases, ranging from cancer to autoimmunity. These diseases are rapidly increasing in number due to our aging population and so new and more effective treatments are required. To maintain this growth in mAb-based treatments and increase their effectiveness we need to better understand their mechanisms of action and develop new antibody formats to overcome any limitations. Amongst these new formats are multi-specific antibodies which have the ability to engage targets simultaneously to drive unique biological responses.mAb depend on their Fc region for function, triggering immune responses following engagement of Fc receptors on immune effector cells. Typically, therapeutic mAbs are of the IfG isotype and so Fc gamma Receptors (FcyRs) are centrally involved in their regulation and mode of action. In humans there are 6 FcyRs; 5 which typically trigger activation of the effector cell and a single inhibitory receptor FcyRIIB, with a similar situation in the mouse.Our recent work has demonstrated that this inhibitory receptor can in fact have very differing effects on mAb immunotherapy, according to the antibody target and/or the specific mAb. Principally, this appears to be related to the ability of FcyRIIB to facilitate higher order clustering of receptors, leading to more potent signalling, however this has not been demonstrated formally. We have also made a surprising observation indicating that FcyRIIB regulates the half-life of mAb and mAb-like reagents such as multi-specifics. The aim of the proposed project is to explore these basic properties of FcyRIIB, to fully elucidate if and how it regulates mAb clustering, whether simple competition with activatory FcyR is involved and how it contributes to mAb half-life. A secondary aim is to develop strategies to potentially overcome these inhibitory aspects to boost mAb immunotherapy. Specifically, using a panel of existing and novel mouse models, lacking FcyRIIB and expressing modified versions of the receptor (eg signalling defective) we will explore how mAb half-life and activity is regulated. This will be achieved using a variety of established and novel mAb formats, designed to understand the molecular basis of the interactions driving the biology. As the FcyR repertoire varies with cell type, location and disease status, these technologies will require careful assessment. For example, the ratio of activatory: inhibitory FcyR may well influence the biology and will be assessed through careful measurement and also the use of mice lacking one or all of the activatory FcyR and/or mice expressing human FcyR. The research outcomes will foster basic understanding of how FcyRIIB regulates mAb half-life and activity, serving to inform the development of more effective mAb therapies and so improve the health of those with diseases such as cancer and autoimmunity. In addition, the tools generated will yield better basic understanding of mAb regulation by FcyRIIB assisting all researchers working with mAb (basic scientists, small biotechs, large pharma developing/producing these reagents).