(340b) Engineering a Cytokine/Antibody Fusion Protein for Targeted Expansion of Regulatory T-Cells
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To overcome challenges in translating anti-cytokine antibody approaches to the clinic, we have developed single-chain IL-2/antibody fusion proteins (known as immunocytokines) that stably and selectively deliver IL-2 to specific immune cell populations. In particular, we leveraged insights from structural biology to engineer a fusion protein that tethers human IL-2 to an anti-IL-2 antibody known as F5111 in order to achieve selective expansion of immunosuppressive regulatory T cells (TRegs). We further applied crystallographic insights to rationally design a panel of immunocytokine variants with a range of potencies in activating human TRegs. In vitro and in vivo studies identified the lead molecule, which shows optimal bias toward expanding TRegs over immune effector cell populations (such as effector T cells and natural killer cells). We are currently testing our lead molecule in mouse models of autoimmune diseases, including colitis and graft-versus-host disease. Our innovative approach presents a translationally relevant and versatile therapy for selective TReg expansion, which can be used for a wide range of research and medical applications.
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