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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.

Author information

1
Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
2
Priority Research Center for Molecular Science &Technology, Ajou University, Suwon 16499, Republic of Korea.
3
Department of Allergy and Clinical Immunology, School of Medicine, Ajou University, Suwon 16499, Republic of Korea.

Abstract

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.

PMID:
28489072
PMCID:
PMC5436137
DOI:
10.1038/ncomms15090
[Indexed for MEDLINE]
Free PMC Article

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