KRAS / MDG2011

MDG2011 is a 3rd-generation TCR-T therapy targeting KRAS (Kirsten rat sarcoma viral oncogene homologue) G12V mutation (mKRAS G12V) co-expressing our PD1-41BB costimulatory switch protein (CSP) which armors and enhances the T cells in the immunosuppressive tumor microenvironment (TME). Preclinical MDG2011 data presented at 2023 ESMO and SITC conferences, demonstrates in vitro elevated effector cytokine functionality with increased and sustained tumor cell killing ability. This data highlighting the enhancement of the TCR-T therapy through the CSP shows MDG2011’s potential to lead to improved clinical outcomes in solid tumors.

Targeting KRAS mutations with TCR-T therapies

Mutations within the KRAS gene display the highest rate in a wide variety of often fatal solid cancer types like pancreatic ductal adenocarcinoma, endometrial, non-small-cell lung, and colorectal cancer. Global incidence of solid tumors expressing KRAS mutations (mKRAS) is estimated to be in excess of 300,000 patients2.  Most prominent mutations arise from a substitution of only one single amino acid (G= glycine) at position 12 to aspartic acid (D), valine (V) or cysteine (C) (Figure 1).
TCR-T cells recognize a wider range of targets, including intra-cellular neoantigens that are not accessible to other T cell-based therapies like CAR-T cells. Mutations within the KRAS gene are unique to cancer cells and absent in healthy normal tissue. The ability to selectively target these mutations with cell therapies can revolutionize treatment options, providing more effective, safer, and durable therapies for patients with high unmet needs.

Figure 1: Frequency of KRAS mutation in different cancer types

  1. ECIS – European Cancer Information System, https://ecis.jrc.ec.europa.eu/
  2. Stephen et al. Dragging Ras Back in the Ring, Cancer Cell 25, March, 2014​

KRAS and immune escape

mKRAS creates a TME affecting immune cells in the TME promoting tumor progression and immune escape (Figure 2). Impact of KRAS mutations in the TME:

  • Increased levels of inflammatory cytokines in the TME necessary for tumor initiation and progression.
  • Elevated expression of Programmed Cell Death 1 Ligand 1 (PD-L1).  PD-1 binds to and inactivates T cells, reduces their proliferation and promotes apoptosis of T cells.
  • Enhanced secretion of chemokine and cytokines facilitating the recruitment of immunosuppressive cells thereby contributing to immune escape.

Figure 2: Mediation of immune espace in the TME by KRAS

Our approach

At Medigene, using our proprietary End-to-End (E2E) Platform, we aim to create a broad KRAS library consisting of multiple T cell receptors targeting different frequent KRAS mutations combined with various HLAs covering broad patient populations with high unmet need. All generated TCRs will be combined with our product enhancement technologies including PD1-41BB and potentially CD40L-CD28 costimulatory switch proteins to enhance the proliferation and persistence of the TCR-T cells and to help mitigate the immunosuppressive effects of the TME.

Find out more about the Medigene´s proprietary E2E Platform here.

 

About KRAS (Kirsten rat sarcoma viral oncogene homologue)

Under physiological conditions the KRAS gene tightly regulates cell proliferation and survival. However, mutations within KRAS result in uncontrolled proliferation of cells. These mutations lead to the generation of so called neoantigens, which are tumor-specific antigens (TSA) promoting growth and maintenance of tumors. KRAS displays the highest mutation rate in a wide variety of often fatal solid cancer types like pancreatic ductal adenocarcinoma, endometrial, non-small-cell lung cancer, and colorectal cancer. Global incidence of solid tumors expressing KRAS mutations (mKRAS) is estimated to be in excess of 300,000 patients. Most prominent mutations arise from a substitution of only one single amino acid (G= glycine) at position 12 to aspartic acid (D), valine (V) or cysteine (C) (Figure 1, 2).

Complete preclinical data of our MDG2011 program lead candidates against mutant KRAS (mKRAS)-specific T cell receptors (TCRs) targeting human leukocyte antigens (HLA) A*11, in combination with a PD1-41BB costimulatory switch protein (CSP) can be found here: SITC 2023

Figure 1: TCR-KRAS-HLA modelling complex

Figure 2: Frequency of KRAS mutations in different cancer types

Figure 3: KRAS mediates immune escape in the TME, in part by upregulating PD-L1 expression

Targeting KRAS mutations with TCR-T therapies

Engineered T cell therapies, such as CAR-T cells, have shown immense potential in treating various malignant diseases in recent years. However, CAR-T cells require the target antigen to be present on the cell surface, which limits their effectiveness. In addition, the target antigen is often expressed on normal healthy cells, increasing the risk of cytotoxic side effects TCR-T cells, on the other hand, recognize a wider range of targets, including neoantigens that are not present on the cell surface and not accessible to CAR-T therapies. Mutations within the KRAS gene result are unique to cancer cells and absent in healthy normal tissue.  Hence, the ability to selectively target these mutations with cell therapies can revolutionize cancer treatment, providing more effective, safer, and personalized therapies for patients with high unmet medical needs.

Our approach

At Medigene we aim to create a broad KRAS library consisting of multiple T cell receptors targeting different KRAS mutations combined with various HLAs covering broad patient populations with high unmet need. All generated TCRs will be further combined with our product enhancement technologies including PD1-41BB and potentially CD40L-CD28 costimulatory switch proteins to enhance the proliferation and persistence of the TCR-T cells and to help mitigate the immunosuppressive effects of the tumor microenvironment.

KRAS and immune escape

Tumors displaying KRAS mutations have been shown to create a tumor microenvironment (TME) affecting immune cells in the TME promoting tumor progression and immune escape. In the presence of KRAS mutations increased levels of inflammatory cytokines have been observed in the TME necessary for tumor initiation and progression.
In additions KRAS mutations have also been associated with elevated expression of Programmed Cell Death 1 Ligand 1 (PD-L1).  PD-1 binds to and inactivates T cells, reduces their proliferation and promotes apoptosis of T cells. Moreover, KRAS mutations promote secretion of various chemokine and cytokines facilitating the recruitment of immunosuppressive cells thereby contributing to immune escape. Overall, KRAS mutations enable various paths to actively affect immune regulation.