The hexavalent CD27 agonist HERA-CD27L increases T-cell activation and induces potent anti-tumor effect
Karl Heinonen, David M. Richards, Christian Merz, Mauricio Redondo-Müller, Viola Marschall Jaromir Sykora, Meinolf Thiemann, Harald Fricke, Christian Gieffers and Oliver Hill
Apogenix AG, Heidelberg, Germany
Tumor necrosis factor receptor superfamily (TNFRSF) proteins are widely expressed by immune and tumor cells highlighting their importance in immuno-oncology. Apogenix has developed a technology platform for the construction of novel hexavalent TNFRSF agonists (HERA). HERA fusion proteins are based on a mimic of the TNFSF cytokine structure and are capable of clustering six receptor chains in a spatially well-defined manner. No secondary clustering through Fc-γ receptors which is required for most agonistic anti-TNFRSF antibodies is needed for in vivo activity with the Apogenix HERA-proteins.
CD27-Ligand (CD70) acts as a potent co-stimulator driving T-cell activation and survival through activation of its receptor (CD27). HERA-CD27L - a human hexavalent CD27 agonist - was expressed in CHO cells followed by a lab-scale purification process resulting in homogenous aggregate-free protein lots. Binding assays showed high affinity binding of the purified protein both to the human and murine receptor. HERA-CD27L binds CD27 expressed on primary human CD4+ and CD8+ T cells and after pre-activation significantly increases T-cell expansion. PK studies in mice revealed a T1/2 of around 13 hours. Using the two colorectal syngeneic murine tumor models MC38-CEA and CT26 in vivo efficacy of HERA-CD27L as single-agent as well as in combination with anti-PD1 was shown. In both models HERA-CD27L treatment resulted in a dose dependent tumor growth inhibition.
In summary, the data on HERA-CD27L indicate a potent immune cell driven anti-tumor efficacy providing the scientific rationale for using HERA-CD27L as a single agent or in combination with check-point inhibitors in cancer therapy.