Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration.
Seung-Min ShinDong-Ki ChoiKeunok JungJeomil BaeJi-Sun KimSeong-Wook ParkKi-Hoon SongYong-Sung KimPublished in: Nature communications (2017)
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.
Keyphrases
- wild type
- transcription factor
- living cells
- endothelial cells
- cancer therapy
- adipose tissue
- immune response
- single molecule
- induced pluripotent stem cells
- oxidative stress
- emergency department
- young adults
- drug delivery
- signaling pathway
- reactive oxygen species
- regulatory t cells
- pluripotent stem cells
- drug induced
- electronic health record
- type iii