Medigene AG Targets KRAS G12V with TCR-guided T Cell Engagers

On December 9, 2024, Medigene AG, an oncology platform company based in Planegg/Martinsried, announced the selection of the KRAS G12V mutation as the initial target for their co-development project with WuXi Biologics. Medigene specializes in T cell receptor (TCR)-guided therapies for cancer treatment, and this collaboration marks a significant milestone in their ongoing efforts.

The KRAS G12V mutation, in the context of HLA*A11, was chosen as the first target for the creation of T cell receptor-guided T cell engagers (TCR-TCEs). This selection is a crucial advancement in the partnership between Medigene and WuXi Biologics, as they aim to develop multiple TCR-TCEs over the next three years. The collaboration seeks to combine Medigene’s expertise in generating highly sensitive, specific, and safe (3S) TCRs with WuXi Biologics’ anti-CD3 monoclonal antibody (mAb) and its proprietary bispecific antibody platform, WuXiBody™.

Selwyn Ho, CEO of Medigene, highlighted the rapid progress in selecting KRAS G12V, also referred to as MDG3010 in Medigene’s pipeline. This step is seen as a pivotal move towards developing a TCR-TCE library aimed at treating challenging tumors. The collaboration between the teams has been highly effective, and there is a strong belief that combining Medigene’s 3S TCR with WuXi Biologics’ CD3 mAb and bispecific platform offers the potential for a best-in-class therapeutic. This therapeutic approach aims to precisely target a broad range of patients expressing the common KRAS mutation, providing an off-the-shelf treatment option.

KRAS mutations are widely recognized as the most common oncogene mutations, playing a significant role in various cancers, including pancreatic, small bowel, colorectal, and lung cancers. In pancreatic cancer, KRAS mutations are present in over 95% of cases, with G12D and G12V being the most frequent. In 2020, pancreatic cancer was the seventh leading cause of cancer-related deaths globally, with nearly as many newly diagnosed cases as deaths.

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

Medigene’s MDG3010 program is the first TCR-TCE therapy in their pipeline, specifically designed to target the KRAS G12V mutation. This program incorporates an optimal TCR selected for its specificity, sensitivity, and safety (3S) in targeting KRAS G12V, paired with WuXi Biologics’ validated anti-CD3 monoclonal antibody. This combination enables potent tumor cell killing while preventing T cell exhaustion.

Mutations in the KRAS gene, which belongs to the group of small GTP-binding proteins known as RAS-like GTPases, are frequently altered in various fatal solid cancer types, such as pancreatic ductal adenocarcinoma, non-small-cell lung cancer, and colorectal cancer. These mutations drive uncontrolled proliferation of cancer cells and are unique to cancer cells, making KRAS an attractive target for TCR-guided therapies. 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 suited for targeting KRAS mutations and other challenging neoantigens in cancer treatment.