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Shin SM
; Choi DK
; Jung K
; Bae J
; Kim JS
; Park SW
; Song KH
; Kim YS
Nat Commun
2017[May]; 8
(?): 15090
PMID28489072
show ga
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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