aKRAS mAbs: a portfolio of aG13D, aG12D and aG12V mAbs intended for treatment of aggressive cancer

      KRAS is the most frequently mutated oncogene in all of human cancers. There is an urgent need to develop effective therapies for the patients harboring KRAS mutations. Oblique has developed a pipeline of aKRAS mAbs targeting the G13D, G12D and G12V KRAS mutations using the Abiprot™ platform. The most advanced program targeting the KRAS G13D mutation has shown efficacy in a G13D mutant colorectal cancer (CRC) xenograft model. In addition to CRC, there are significant patient populations with KRAS mutations in Pancreatic, Lung, Melanoma and several other malignancies. Thus, these mutant selective antibodies could prove useful to treat tumor types harboring KRAS mutations.

      In parallel to developing the mAbs as therapeutics, Oblique is partnering with Targovax in delivering these KRAS antibodies intracellularly through oncolytic viral vectors. https://obliquet.com/wp-content/uploads/2020/06/Oblique-Therapeutics-and-Targovax-enter-collaboration-to-target-mutant-RAS.pdf

      About KRAS-mutated cancers

      According to recent estimates from WHO, around 1.93 million people develop colorectal cancer (CRC) with 935,000 people succumbing to the disease in 2020, making it the third-most prevalent and second-most deadly cancer in the world. Approximately 50% of CRC patients harbor mutations in KRAS with G12D, G12V and G13D contributing to ~30%. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and chemo-resistant human cancers and is among the leading causes of cancer related mortality. Nearly all patients with PDAC harbor KRAS mutations with G12D and G12V contributing to ~ 75% of the total. Lung cancer which is the leading cause of cancer related mortality worldwide (1.8 million deaths in 2020) is caused by oncogenic KRAS mutations in ~ 30% of patients. Mutations in G12D, G12V and G13D contribute to ~ 10% of the total KRAS mutations. Although significant progress has been made in colorectal and lung cancer treatments for broader KRAS WT patient population in the last few decades, effective treatment options are very few for KRAS mutant patients and prognosis remains poor. In PDAC, there are very few effective treatments with most available treatments being palliative. Thus, there is a huge unmet medical need that calls for innovative new therapies that target the unique underlying molecular drivers of the disease.

      References

      • Trkulja C.L. et al; Rational Antibody design for Undruggable Targets using Kinetically Controlled Biomolecular Probes. Science Advances 16 Apr 2021; Vol. 7, no. 16, eabe6397.
      • https://www.who.int/news-room/fact-sheets/detail/cancer
      • Wilson PM, Labonte MJ, Lenz HJ. Molecular markers in the treatment of metastatic colorectal cancer. Cancer J. 2010 May-Jun. 16(3):262-72.
      • Porru, Manuela, et al. “Targeting KRAS in metastatic colorectal cancer: current strategies and emerging opportunities.” Journal of Experimental & Clinical Cancer Research 37.1 (2018): 57.
      • Datamonitor Healthcare Colorectal Cancer Patient based Forecast Report 2016-2015