Medigene AG, a company specializing in oncology platforms aimed at the exploration and advancement of T cell receptor-directed therapies for cancer treatment, has unveiled its choice of Kirsten rat sarcoma viral oncogene homologue (KRAS) G12V, under the context of HLA A11, as the first focal point for the collaborative development of T cell receptor-directed T cell engagers (TCR-TCEs) alongside WuXi Biologics.
This decision marks a significant milestone for the Medigene and WuXi Biologics alliance, intending to forward multiple TCR-TCEs over the next few years. Their collaboration is poised to leverage Medigene’s proficiency in producing and detailing highly sensitive, specific, and safe (3S) TCRs, along with WuXi Biologics’ innovative anti-CD3 monoclonal antibody (mAb), its TCE framework, and the proprietary bispecific antibody platform known as WuXiBody.
Selwyn Ho, the CEO of Medigene, remarked, “Swift selection of KRAS G12V as the target for the introductory programme, recognized as MDG3010 within Medigene’s initiatives, signifies the groundwork for constructing a TCR-TCE repository for hard-to-treat tumors. This accelerated programme advancement manifests the highly efficient partnership between the involved teams. We anticipate that combining Medigene’s 3S TCR with WuXi Biologics’ CD3 mAb and bispecific platform has the potential to offer a superior therapeutic targeting broad patient groups who exhibit this validated and common KRAS mutation, via an accessible administration model.”
KRAS mutations have become renowned as the most prevalent oncogene mutations, significantly influencing conditions affecting many patients, including pancreatic, small bowel, colorectal, and lung cancers. In the realm of pancreatic cancer, KRAS mutations represent some of the foremost and most vital genetic variations, detected in over 95% of cases. Among these, G12D and G12V mutations are most prominent (~65%). In 2020, pancreatic cancer ranked as the seventh leading cause of cancer-related deaths globally for both men and women, with nearly equal numbers of new diagnoses (496,000) and deaths (466,000) from this specific type.
The bispecific therapies industry offers a substantial avenue for combating cancer, addressing the unsolved needs within both solid and hematologic tumors. An excess of 5 million cancer patients globally face discouraging five-year survival rates, underscoring the urgent requirement for pioneering treatments. Bispecific TCR-TCEs, leveraging the immune system for precise cancer cell targeting, are expected to witness a compound annual growth rate of 40.9% from 2023 to 2030. By 2030, the market is projected to exceed USD 80 billion, denoting its capacity to revolutionize cancer therapies and enhance patient prognoses.
TCR-directed T cell engagers (TCR-TCEs) signify a revolutionary ‘off-the-shelf’ immunotherapy exploiting TCR specificity in recognizing cancer cells and directing T cells toward them. Distinct from conventional antibodies, TCRs are capable of recognizing both intracellular and extracellular targets presented by peptide-HLA complexes on cancerous cells, permitting a broader range of targetable antigens.
Within its Comprehensive Platform, Medigene discovers natural TCR sequences embodying high specificity, sensitivity, and safety (3S). These quintessential 3S TCRs can be integrated with a Cluster of Differentiation 3 (CD3) T cell engaging antibody.
The TCR-TCEs uniquely divert the patient’s T cells towards the cancer cells via the binding of the 3S TCR to a target (cancer-testis antigen or neoantigen) predominantly found on tumor cells. When brought in proximity to cancer cells, the T cells are activated through the anti-CD3 monoclonal antibody (mAb), leading to cytokine and cytotoxic molecule release for cancer cell eradication.
Creating highly specific TCR-TCEs offers ‘off-the-shelf’ anti-cancer treatments with potential to emulate or supplement the anti-cancer impacts of adoptive cell therapies.
MDG3010 stands as the pioneer TCR-TCE therapy initiative within Medigene’s pipeline, purposefully designed to target the KRAS (Kirsten rat sarcoma viral oncogene homologue) G12V neoantigen, chosen from one of the TCR prospects in Medigene’s KRAS-targeting TCR repository. KRAS G12V frequently emerges as a mutated gene in cancer, often associated with severe disease and poor prognosis, especially in relapsed cases.
MDG3010 encompasses an optimal TCR chosen for specificity, sensitivity, and safety (3S) aimed at KRAS G12V, paired with WuXi Biologics’ unique and esteemed anti-CD3 monoclonal antibody (mAb), facilitating potent tumor cell devitalization while averting T cell exhaustion.
KRAS (Kirsten rat sarcoma viral oncogene homologue) is part of a group known as small Guanosine-5′-triphosphate (GTP)-binding proteins, classified as RAS-like GTPases. In physiological conditions, KRAS meticulously controls cell proliferation and survival.
In cancer scenarios, KRAS is frequently mutated across a plethora of grave solid cancer types, including pancreatic ductal adenocarcinoma, non-small-cell lung cancer, and colorectal cancers. Mutations in the KRAS gene result in neoantigens’ formation, driving uncontrolled cancer cell proliferation. These mutations within the KRAS gene are singular to cancer cells and absent in healthy regular tissue, rendering KRAS an appealing target for TCR-directed therapies.
TCR-directed therapies proffer a promising way to target these mutations, overcoming the issues posed by solid tumors. Unlike CAR-T cells, which constrain to surface antigens for recognition and may face limitations in target accessibility, TCRs discern a wider array of targets, including intracellular proteins like KRAS neoantigens. This distinctive capability renders TCR-directed therapies eminently suited for challenging neoantigen targeting, such as KRAS mutations.
Medigene AG, an immuno-oncology platform entity, commits to developing T cell receptor-directed therapies to efficiently combat cancer. Its comprehensive platform cultivates optimal 3S (sensitive, specific, and safe) T cell receptors with unique and notable traits applicable across multiple therapeutic modalities. These modalities include off-the-shelf TCR-directed 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).