Selective expansion of regulatory T cells by kidney-tethered IL2 mutein

Abstract

Abstract Regulatory T cells (Treg) play a critical role in maintaining graft tolerance following organ transplantation, and increased numbers of Tregs in solid-tissue grafts such as the kidney are associated with improved graft survival and function. Therapeutic approaches that increase Tregs offer a promising alternative to current standard-of-care treatment consisting of broad-acting immunosuppressants and their attendant side effects. While efforts to expand Tregs ex vivo for infusion into patients have shown promise, they present manufacturing and administration challenges. Low dose (LD) interleukin 2 (IL-2) drives Treg proliferation and function via the heterotrimeric IL-2 receptor expressed on Tregs and has been shown to expand Tregs in vivo, including in the context of transplantation. However, IL-2 can also activate other immune cells including conventional T cells and Natural Killer (NK) cells, which express IL-2Rb/CD122 and IL-2g/CD132, and this could accelerate rejection. We have enhanced IL-2 selectivity for Treg by introducing mutations that increase affinity for CD25 and decrease affinity for CD122/CD132, resulting in Treg specific expansion. Here, we demonstrate that this IL-2 Mutein (IL-2M) can be “tethered” to the kidney via a bifunctional antibody targeting a tubule-specific protein. This kidney-tethered IL-2M maintains Treg selectivity and localizes to the kidney with extended tissue PK. Moreover, in a CD34-NSG mouse model, animals dosed with kidney-tethered IL-2M exhibited prolonged kidney Treg expansion compared to a systemic, non-tethered IL-2M. This approach has the potential to substantially improve kidney graft acceptance while reducing adverse effects and improving patient quality of life.