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PDBsum entry 4leo
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Transferase/immune system
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PDB id
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4leo
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Contents |
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214 a.a.
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219 a.a.
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601 a.a.
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References listed in PDB file
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Key reference
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Title
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Rg7116, A therapeutic antibody that binds the inactive her3 receptor and is optimized for immune effector activation.
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Authors
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C.Mirschberger,
C.B.Schiller,
M.Schräml,
N.Dimoudis,
T.Friess,
C.A.Gerdes,
U.Reiff,
V.Lifke,
G.Hoelzlwimmer,
I.Kolm,
K.P.Hopfner,
G.Niederfellner,
B.Bossenmaier.
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Ref.
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Cancer Res, 2013,
73,
5183-5194.
[DOI no: ]
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PubMed id
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Abstract
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The EGF receptor (EGFR) HER3 is emerging as an attractive cancer therapeutic
target due to its central position in the HER receptor signaling network. HER3
amplifies phosphoinositide 3-kinase (PI3K)-driven tumorigenesis and its
upregulation in response to other anti-HER therapies has been implicated in
resistance to them. Here, we report the development and characterization of
RG7116, a novel anti-HER3 monoclonal antibody (mAb) designed to block HER3
activation, downregulate HER3, and mediate enhanced antibody-dependent
cell-mediated cytotoxicity (ADCC) via glycoengineering of the Fc moiety.
Biochemical studies and X-ray crystallography revealed that RG7116 bound
potently and selectively to domain 1 of human HER3. Heregulin binding was
prevented by RG7116 at concentrations more than 1 nmol/L as was nearly complete
inhibition of HER3 heterodimerization and phosphorylation, thereby preventing
downstream AKT phosphorylation. In vivo RG7116 treatment inhibited xenograft
tumor growth up to 90% relative to controls in a manner accompanied by
downregulation of cell surface HER3. RG7116 efficacy was further enhanced in
combination with anti-EGFR (RG7160) or anti-HER2 (pertuzumab) mAbs. Furthermore,
the ADCC potency of RG7116 was enhanced compared with the nonglycoengineered
parental antibody, both in vitro and in orthotopic tumor xenograft models, where
an increased median survival was documented. ADCC degree achieved in vitro
correlated with HER3 expression levels on tumor cells. In summary, the
combination of strong signaling inhibition and enhanced ADCC capability rendered
RG7116 a highly potent HER3-targeting agent suitable for clinical development.
Cancer Res; 73(16); 5183-94. ©2013 AACR.
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