A novel TNFR2 agonist antibody expands highly potent regulatory T cells

Regulatory T cells (T-reg cells) restrict immune system activity, such as in response to self-antigens, and are switched on by tumor necrosis factor receptor 2 (TNFR2). Therapeutic activation of TNFR2, thereby expanding T-reg cells and suppressing immune activity, may be beneficial to patients with various inflammatory diseases. Here, we characterized a new human TNFR2-directed antibody agonist isolated from mice. We found that the antibody agonist expanded the number of T-reg cells within cultures of primary human CD4(+) T cells from healthy donors and patients with type 1 diabetes or Sezary syndrome. These T-reg cells had increased metabolic gene expression and intracellular itaconate concentrations, characteristics associated with maximally suppressive, anti-inflammatory T-reg cells. Furthermore, antibody-expanded T-reg cells repressed the activity of primary human CD8(+) effector T cells (T-eff cells). Epitope mapping suggested that the antibody bound to TNFR2 through a natural cross-linking surface and that T-reg cell expansion was independent of the antibody Fc region. In addition, T-reg cell expansion was not increased by adding either supplemental TNF ligand or a cross-linking reagent, suggesting that the antibody agonist by itself can elicit maximal activity, a notion that was confirmed by increased secretion of soluble TNFR2. Pending in vivo tests, these features indicate that this TNFR2 antibody agonist has the potential to safely and effectively treat various inflammatory disorders.