Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration

摘要: Oncogenic Ras mutants, frequently detected in human cancers, are high-priority anticancer drug targets. However, direct inhibition of oncogenic mutants with small molecules has been extremely challenging. Here we report the development a IgG1 format antibody, RT11, which internalizes into cytosol living cells and selectively binds to activated GTP-bound form various block interactions effector proteins, thereby suppressing downstream signalling exerting anti-proliferative effects variety tumour harbouring mutants. When systemically administered, an RT11 variant additional tumour-associated integrin binding moiety for tissue targeting significantly inhibits vivo growth Ras-mutated xenografts mice, but not wild-type Ras-harbouring tumours. Our results demonstrate feasibility developing therapeutic antibodies cytosolic proteins that inaccessible using current antibody technology.