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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies, Monoclonal / pharmacology*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects*
-
Cytosol / metabolism*
-
GTP Phosphohydrolases / antagonists & inhibitors
-
GTP Phosphohydrolases / genetics
-
GTP Phosphohydrolases / metabolism
-
HL-60 Cells
-
HT29 Cells
-
HeLa Cells
-
Humans
-
Immunoglobulin G / pharmacology*
-
K562 Cells
-
MCF-7 Cells
-
Membrane Proteins / antagonists & inhibitors
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism
-
Mice
-
Mutation
-
NIH 3T3 Cells
-
Neoplasm Transplantation
-
Neoplasms / drug therapy
-
Neoplasms / genetics*
-
Protein Interaction Domains and Motifs
-
Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
-
Proto-Oncogene Proteins p21(ras) / genetics
-
Proto-Oncogene Proteins p21(ras) / metabolism
-
Signal Transduction / drug effects
-
Xenograft Model Antitumor Assays
-
ras Proteins / antagonists & inhibitors
-
ras Proteins / genetics*
-
ras Proteins / metabolism
Substances
-
Antibodies, Monoclonal
-
Immunoglobulin G
-
KRAS protein, human
-
Membrane Proteins
-
GTP Phosphohydrolases
-
NRAS protein, human
-
HRAS protein, human
-
Proto-Oncogene Proteins p21(ras)
-
ras Proteins