Medigene AG Announces KRAS G12V as First Target for TCR-Guided T Cell Engagers

Medigene AG recently announced the selection of Kirsten rat sarcoma viral oncogene homologue (KRAS) G12V, in the context of HLA*A11, as the initial target for the co-development of T cell receptor-guided T cell engagers (TCR-TCEs) with WuXi Biologics.

The selection of this first target is a key step for the partnership between Medigene and WuXi Biologics, which aims to advance multiple TCR-TCEs over the next three years. The collaboration seeks to harness Medigene’s expertise in the generation and characterization of highly sensitive, specific and safe (3S) TCRs with WuXi Biologics’ unique anti-CD3 monoclonal antibody (mAb), its TCE platform and proprietary bispecific antibody platform WuXiBody.

“Rapid selection of KRAS G12V as the target for this first program, also known as MDG3010 in Medigene’s pipeline, marks the initial step for the development of a TCR-TCE library for the treatment of difficult-to-treat tumors. This fast program progression reflects the highly effective collaboration between the teams,” said Selwyn Ho, CEO of Medigene. “We believe that the combination of Medigene’s 3S TCR and WuXi Biologics’ CD3 mAb and bispecific platform offers the potential of a best-in-class therapeutic that precisely targets broad numbers of patients expressing this validated common KRAS mutation, in an off-the-shelf administration.”

KRAS mutations are widely recognized as the most common oncogene mutations and play a significant role in indications that affect a large number of patients, such as pancreatic, small bowel, colorectal, and lung cancers. In pancreatic cancer, KRAS mutations are among the earliest and most critical genetic alterations, present in over 95% of cases; here, G12D and G12V are the most frequent (~65%). In 2020, pancreatic cancer was the seventh leading cause of cancer-related deaths globally for both men and women, with nearly as many newly diagnosed patients (496,000) as deaths (466,000) from this single indication.

The bispecific therapies market offers a significant opportunity in the fight against cancer, addressing the unmet need in both solid and hematologic tumors. Over 5 million cancer patients worldwide face low 5-year survival rates, highlighting the urgent demand for innovative treatments. Bispecific TCR-TCEs, which harness the immune system to target cancer cells more precisely, are projected to grow at a compound annual rate of 40.9% from 2023 to 2030. By 2030, the market is expected to surpass USD 80 billion, reflecting its potential to transform cancer treatment and improve patient outcomes.

Medigene AG (FSE: MDG1) is an immuno-oncology platform company dedicated to developing T cell receptor (TCR)-guided therapies to effectively eliminate cancer. Its End-to-End Platform generates optimal 3S (sensitive, specific and safe) T cell receptors with unique and distinctive attributes that can be utilized in multiple therapeutic modalities, such as off-the-shelf TCR-guided T cell engager (TCR-TCE) therapies (MDG3010), TCR-natural killer cell (TCR-NK) therapies and T cell receptor engineered T cell (TCR-T) therapies (MDG1015). For more information, visit https://medigene.com/.

TCR-guided T cell engagers (TCR-TCEs) represent an innovative ‘off-the-shelf’ immunotherapy that leverages the specificity of TCRs recognize cancer cells and guide T cells towards them. Unlike conventional antibodies, TCRs can recognize both intracellular and extracellular targets presented by peptide-HLA complexes on cancer cells, allowing for a broader range of targetable antigens.

As part of its End-To-End Platform, Medigene discovers natural TCR sequences with high specificity, sensitivity and safety (3S). These optimal 3S TCRs can subsequently be merged with a Cluster of Differentiation 3 (CD3) T cell engaging antibody.

The TCR-TCEs specifically redirect the patient’s own T cells towards the cancer cells via binding of the 3S TCR to a target (cancer-testis antigen or neoantigen) that is almost exclusively present on tumor cells. The T cells, when brought into proximity of cancer cells, are activated through the anti-CD3 monoclonal antibody (mAb), leading to release of cytokines and cytotoxic molecules that facilitate cancer cell killing.

Development of highly specific TCR-TCEs provides “off-the-shelf” anti-cancer agents with potential to achieve similar or complementary anti-cancer effects to those of adoptive cell therapies.

MDG3010 is the first TCR-TCE therapy program in Medigene´s pipeline and is specifically designed to target the neoantigen KRAS (Kirsten rat sarcoma viral oncogene homologue) G12V, selected from one of the TCR candidates within Medigene’s KRAS-targeting TCR library. KRAS G12V is one of the most frequently mutated genes in cancer, often associated with aggressive disease and poor prognosis, particularly in cases of relapse.

MDG3010 incorporates an optimal TCR selected for specificity, sensitivity and safety (3S) targeting KRAS G12V, paired with WuXi Biologics unique and validated anti-CD3 monoclonal antibody (mAb), that enables potent tumor cell killing while preventing T cell exhaustion.

KRAS (Kirsten rat sarcoma viral oncogene homologue) belongs to the group of small so-called Guanosine-5′-triphosphate (GTP)-binding proteins, known as RAS-like GTPases. Under physiological conditions KRAS tightly regulates cell proliferation and survival.

In cancer, KRAS is found frequently altered, in a wide variety of often fatal solid cancer types like pancreatic ductal adenocarcinoma, non-small-cell lung cancer, and colorectal cancer. Mutations in the KRAS gene result in the creation of neoantigens that drive uncontrolled proliferation of cancer cells. These mutations within the KRAS gene are unique to cancer cells and absent in healthy normal tissue, making KRAS an attractive target for TCR-guided therapies. TCR-guided therapies offer a promising approach to targeting these mutations and addressing the challenges posed by solid tumors. Unlike CAR-T cells, which require surface antigens for recognition and may have limitations in target accessibility, TCRs recognize a broader range of targets including intracellular proteins like KRAS neoantigens. This unique ability makes TCR-guided therapies particularly well-suited for targeting KRAS mutations and other challenging neoantigens.