Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties

• DOI: 10.4049/jimmunol.2000704
• Publication Date: 2021-09-22T17:30:35Z
• Authors: Valentina Ceglia; Sandra Zurawski; Monica Montes; Aurélie Bouteau; Zhiqing Wang; Jerome Ellis; Botond Z Igyártó; Yves Lévy; Gerard Zurawski
• Keywords: CD154

CD40 is a potent activating receptor within the TNFR family expressed on APCs of immune system, and it regulates many aspects B T cell immunity via interaction with ligand (CD40L; CD154) surface activated cells. Soluble CD40L agonistic mAbs directed to are being explored as adjuvants in therapeutic or vaccination settings. Some anti-CD40 Abs can synergize soluble monomeric CD40L. We show that direct fusion certain confers superagonist properties, reducing dose required for efficacy, notably greatly increasing total cytokine secretion by human dendritic The tetravalent configuration anti-CD40-CD40L promotes clustering internalization likely mechanism increased activation. fused either L H chain C termini, without flexible linkers, were all superagonists greater potency than trimer. Ab was independent higher order aggregation. Moreover, showed vivo transgenic mice compared parental Ab. To broaden concept fusing natural ligand, we OX40L an OX40 Ab, this resulted dramatically efficacy proliferation production CD4+ cells well releasing from dependency cross-linking. This work shows directly antireceptor useful strategy increase agonist potency.