Format

Send to

Choose Destination
Biosci Rep. 2017 Nov 29. pii: BSR20171278. doi: 10.1042/BSR20171278. [Epub ahead of print]

A novel bispecific c-MET/CTLA-4 antibody targeting lung cancer stem cell-like cells with therapeutic potential in human non-small cell lung cancer.

Author information

1
Department of Radiation Oncology, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
2
Department of Respiratory Medicine, The Eastern Hospital of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
3
Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
4
Department of Geriatrics, National Key Clinical Specialty, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China liufengabby@163.com.

Abstract

A novel paradigm in tumor biology suggests that non-small cell lung cancer (NSCLC) growth is driven by lung cancer stem cell-like cells (LCSCs), but here are still not any effective strategies to remove LCSCs. The bispecific antibody is a novel antibody, which can target two different antigens and mediate specific killing effects by selectively redirecting effector cells to the target cells. Here, we designed and synthesized a new bispecific antibody (BsAb), BsAb-5, that can target cellular-mesenchymal to epithelial transition factor (c-MET) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) in CD166+ LCSCs with high affinity and specificity, for the first time. We showed that BsAb-5 could inhibit hepatocyte growth factor (HGF)-mediated tumor development, including proliferation, migration, and apoptosis, serving as an inhibitory c-MET antibody. Moreover, we demonstrated that mechanisms responsible for BsAb-5 in CD166+ LCSCs included inducing c-MET degradation and inhibition HGF-stimulated c-MET-Notch pathway by using AdHGF infection, nuclei location and western-blot assays. In vivo, xenograft analysis revealed that mice on BsAb-5 group showed significantly reduced tumor volume. At the meantime, the observed anti-tumor effects of BsAb-5 were dependent on considerably suppressing Tregs and up-regulating effector T cells. On the basis of these results, we have identified a potential bispecific antibody drug, which can effectively target c-MET and CTLA-4 in CD166+ LCSCs for the treatment of human NSCLC.

KEYWORDS:

CD166; CTLA-4; bispecific antibody; c-MET; lung cancer stem cell-like cells; non-small cell lung cancer

PMID:
29187584
DOI:
10.1042/BSR20171278

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center