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Nat Commun. 2017 May 10;8:15090. doi: 10.1038/ncomms15090.

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

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Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
Priority Research Center for Molecular Science &Technology, Ajou University, Suwon 16499, Republic of Korea.
Department of Allergy and Clinical Immunology, School of Medicine, Ajou University, Suwon 16499, Republic of Korea.


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

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