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LY2875358, a Neutralizing and Internalizing Anti-MET Bivalent Antibody, Inhibits HGF-Dependent and HGF-Independent MET Activation and Tumor Growth
- Source :
- Clinical Cancer Research. 20:6059-6070
- Publication Year :
- 2014
- Publisher :
- American Association for Cancer Research (AACR), 2014.
-
Abstract
- Purpose: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms. Experimental Design/Results: Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody. Conclusions: LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies. Clin Cancer Res; 20(23); 6059–70. ©2014 AACR.
- Subjects :
- Male
Cancer Research
media_common.quotation_subject
Down-Regulation
Antineoplastic Agents
Biology
Antibodies, Monoclonal, Humanized
Mice
Downregulation and upregulation
Cell Line, Tumor
Neoplasms
medicine
Animals
Humans
Phosphorylation
Receptor
Autocrine signalling
Internalization
Cell Proliferation
media_common
Hepatocyte Growth Factor
Cell growth
Antibodies, Monoclonal
Proto-Oncogene Proteins c-met
Antibodies, Neutralizing
Xenograft Model Antitumor Assays
Molecular biology
Tumor Burden
Enzyme Activation
Disease Models, Animal
Macaca fascicularis
Protein Transport
Oncology
Mechanism of action
Cell culture
Proteolysis
Cancer research
Female
Hepatocyte growth factor
medicine.symptom
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....9aa11a2aca8597fa77410f90fb34f2ff