9^th European Immunology Conference associated with Antibody Engineering Meeting

Ras proteins (KRas, HRas, and NRas) are small GTPases that function as molecular switches at the inner plasma membrane by alternating between GTP-bound active forms (Ras-GTP) and GDP-bound (Ras-GDP) inactive forms. Oncogenic mutations in Ras proteins, predominantly found at G12, G13, and Q61 residues, impair the GTPase activity rendering the mutants persistently GTP-bound active form, thereby promoting tumorigenesis and tumor malignancy. Oncogenic Ras mutants, frequently detected in human cancers, are high-priority anticancer drug targets. However, direct inhibition of oncogenic Ras mutants with small molecules has been extremely challenging. In this talk, I will present the development of a human IgG1 format antibody, named iMab (internalizing & protein-protein interaction (PPI) interfering monoclonal antibody), which directly targets the intracellularly activated GTP-bound form of various oncogenic Ras mutants aft er internalization into the cytosol of living cells. iMab specifi cally binds to the PPI interfaces between activated Ras and eff ector proteins such as Raf and PI3K to block the associations, thereby suppressing downstream signaling and exerting anti-proliferative eff ects in a variety of tumor cells harboring oncogenic Ras mutants. When systemically administered, an iMab variant with an additional tumor-associated integrin binding moiety for tumor tissue targeting signifi cantly inhibited the in vivo growth of oncogenic Ras-mutated tumor xenograft s in mice, but not wild-type Ras-harboring tumors. Our results demonstrate the feasibility of developing therapeutic antibodies for direct targeting of cytosolic proteins that are inaccessible using current antibody technology.