A novel TNFR2 agonist antibody expands highly potent regulatory T cells

Regulatory T cells (Treg 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 Treg 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
Treg cells within cultures of primary human CD4+ T cells
from healthy donors and patients with type 1 diabetes or Sézary syndrome.
These Treg cells had increased metabolic gene expression and
intracellular itaconate concentrations, characteristics associated with
maximally suppressive, anti-inflammatory Treg cells. Furthermore,
antibody-expanded Treg cells repressed the activity of primary
human CD8+ effector T cells (Teff cells). Epitope
mapping suggested that the antibody bound to TNFR2 through a natural
cross-linking surface and that Treg cell expansion was
independent of the antibody Fc region. In addition, Treg 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.

调节性T细胞（Regulatory T cells, Treg细胞）可限制免疫系统活性，例如针对自身抗原的应答，并可通过肿瘤坏死因子受体2（tumor necrosis factor receptor 2, TNFR2）被激活。通过治疗性激活TNFR2以扩增Treg细胞并抑制免疫活性，或可使多种炎症性疾病患者获益。本研究对一种从小鼠中分离得到的新型人源TNFR2靶向抗体激动剂进行了表征。我们发现，该抗体激动剂可在健康供者、1型糖尿病患者以及塞扎里综合征患者的原代人CD4阳性T细胞培养体系中实现Treg细胞数量的扩增。此类Treg细胞的代谢相关基因表达水平与胞内衣康酸浓度均有所升高，这一特征与具有最强抑制活性的抗炎性调节性T细胞相一致。此外，经该抗体扩增的Treg细胞可抑制原代人CD8阳性效应T细胞（CD8+ effector T cells, Teff细胞）的活性。表位作图结果显示，该抗体通过天然交联表面结合TNFR2，且Treg细胞的扩增不依赖于抗体的Fc区域。此外，添加外源性TNF配体或交联试剂均未增强Treg细胞的扩增，提示该抗体激动剂本身即可发挥最大活性，这一结论得到了可溶性TNFR2分泌量升高的验证。在开展体内试验之前，上述特征表明这款TNFR2抗体激动剂具备安全且有效治疗多种炎症性疾病的潜力。