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

Seung-Min Shin, Dong-Ki Choi, Keunok Jung, Jeomil Bae, Ji-sun Kim, Seong-wook Park, Ki-Hoon Song and Yong-Sung Kim ()
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Seung-Min Shin: Ajou University
Dong-Ki Choi: Ajou University
Keunok Jung: Priority Research Center for Molecular Science & Technology, Ajou University
Jeomil Bae: Ajou University
Ji-sun Kim: Ajou University
Seong-wook Park: Ajou University
Ki-Hoon Song: School of Medicine, Ajou University
Yong-Sung Kim: Ajou University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15090

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