Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and Anti-Tumor Activity

摘要

Agonistic antibodies targeting the tumor necrosis factor(TNF) superfamily of co-stimulatory receptors(TNFRSF) are progressing through various stages ofclinical development for cancer treatment, but thedesired and defining features of these agents foroptimal biological activity remain controversial.One idea, based on recent studies with CD40, isthat non-ligand-blocking antibodies targeting membrane-distalcysteine-rich domain 1 (CRD1) havesuperior agonistic activities compared with ligandblockingantibodies targeting more membrane-proximalCRDs. Here, we determined the binding andfunctional characteristics of a panel of antibodies targetingCRDs 1–4 of OX40 (also known as TNFRSF4 orCD134). In striking contrast to CD40, we found thatligand-blocking CRD2-binding and membrane-proximalCRD4-binding anti-OX40 antibodies have thestrongest agonistic and anti-tumor activities. Thesefindings have important translational implicationsand further highlight that the relationship betweenepitope specificity and agonistic activity will be animportant issue to resolve on a case-by-case basiswhen optimizing antibodies targeting different costimulatorytumor necrosis factor receptors (TNFRs).