PD1-41BB Costimulatory Switch Protein

The PD1-41BB costimulatory switch protein impedes tumor immune escape (“Immune evasion”), a phenomenon allowing cancer cells to proliferate and metastasize without being recognized by the host immune system. Immune evasion is one of the major challenges in immunotherapy.

The PD-1/PD-L1 signaling pathway 

Programmed cell death protein 1 (PD-1) is an inhibitory checkpoint molecule expressed on T and B cells that plays a major role in the regulation of immune responses facilitating immune evasion. Under normal conditions, the PD-1/PD-L1 pathway plays an important role in suppression of the human immune system to prevent autoimmune diseases. However, in cancer, tumors trick the immune system by expressing Programmed Cell Death Ligand 1 (PD-L1), which binds to PD-1 on T cells resulting in a transmission of a inhibitory signal that inactivates T cells, reduces their proliferation and promotes apoptosis (cell death) in T cells. This interaction has been shown to negatively impact efficient killing of cancer cells by T cells in the tumor microenvironment (TME) by reducing T cell activation, promoting irreversible T cell exhaustion and induction of apoptosis of tumor-reactive T cells.

The role of PD1-41BB costimulatory switch protein in T cell signalling

To enhance T cell functionality in the TME and to overcome the inhibitory signal by the PD1-PDL1 axis used by tumor cells, we combine our highly specific TCRs with a PD1-41BB receptor. The PD1-41BB costimulatory switch protein consists of the extracellular domain of PD-1 and the signaling domain of 4-1BB which turns the inhibitory signal into an activation signal. This enables Medigene TCR-T cell therapies to have the potential to kill more cancer cells through multiple mechanisms (Figure 1). Combination of our TCRs with PD1-41BB costimulatory switch protein increases T cell proliferation / functionality leading to elevated tumor cell killing, allows us to generate best-in-class TCRs with increased efficacy and safety, which can be applied to patients suffering from different types of cancer.

Figure 1:
Single Technology to Provide Sustainable T Cell Enhancement Through Multiple Mechanisms

Release of interferon γ as a surrogate parameter of T cell activation is higher with MDG1015 as compared to the Naked TCR. MDG1015 displays superior recognition of NY-ESO-1 and PD-L1 positive cancer cells (Figure 2).

In serial killing assays directed against two different Cancer-Testis Antigens (PRAME and NY-ESO-1) TCR-T cells  co-expressing TCR+PD1-41BB switch receptor displayed faster killing of 3D tumor spheroids as compared to the Naked TCR (Figure 3).

Figure 2:
Tumor cell recognition and T cell activation with MDG1015 vs. Naked TCR

Figure 3:
Serial killing assays TCR+PD1-41BB vs. Naked TCR