Agonist immunostimulatory antibodies (IS-Abs)
The reactivity of immune cells is regulated by a great diversity of cell surface receptors. We identified CD40, OX40 (CD134) and 4-1BB (CD137), all members of the tumor necrosis factor-receptor (TNFR) family, as the most interesting targets for agonist IS-Ab based on the following criteria:
efficacy: striking pre-clinical evidence for therapeutic impact against tumors
safety: the expectation that immune related adverse events will be manageable
complementarity: enhancement of anti-cancer immunity through distinct mechanisms
The mechanism of action of anti-CD40 Abs primarily involves direct stimulation of innate myeloid cells and indirect enhancement of T-cell immunity through activation of dendritic cells, which makes this pathway complementary to direct T-cell stimulation by agonist IS-Abs against OX40 and 4-1BB. Anti-4-1BB Abs primarily stimulate CD8+ T-killer cells, whereas anti-OX40 Abs primarily potentiate the CD4+ T-helper response and were found to suppress CD4+ T-regulatory cells. Importantly, T-cell stimulation through OX40 and 4-1BB is less potent than that mediated by the major co-stimulatory receptor CD28, and their triggering in the absence of T-cell receptor stimulation was not found to result in T-cell activation. Furthermore, OX40 and 4-1BB are – unlike CD28 - not constitutively expressed at the T-cell surface. This significantly reduces the risks of serious adverse events due to uncontrolled immune cell activation.