Influence of antigen density and immunosuppressive factors on tumor-targeted costimulation with antibody-fusion proteins and bispecific antibody-mediated T cell response.

Target expression heterogeneity and the presence of an immunosuppressive microenvironment can hamper severely the efficiency of immunotherapeutic approaches. We have analyzed the potential to encounter and overcome such conditions by a combinatory two-target approach involving a bispecific antibody retargeting T cells to tumor cells and tumor-directed antibody-fusion proteins with costimulatory members of the B7 and TNF superfamily. Targeting the tumor-associated antigens EpCAM and EGFR with the bispecific antibody and costimulatory fusion proteins, respectively, we analyzed the impact of target expression and the influence of the immunosuppressive factors IDO, IL-10, TGF-β, PD-1 and CTLA-4 on the targeting-mediated stimulation of T cells.

Tumor-targeted costimulation with antibody-fusion proteins improves bispecific antibody-mediated immune response in presence of immunosuppressive factors.

Therapeutic strategies aiming for the induction of an effective immune response at the tumor site can be severely hampered by the encounter of an immunosuppressive microenvironment. We investigated here the potential of concerted costimulation by tumor-directed antibody-fusion proteins with B7.1, 4-1BBL and OX40L to enforce bispecific antibody-induced T cell stimulation in presence of recognized immunosuppressive factors including IL-10, TGF-β, indoleamine 2,3-dioxygenase (IDO), PD-L1 and regulatory T cells.