A novel bispecific c-MET/CTLA-4 antibody targetting lung cancer stem cell-like cells with therapeutic potential in human non-small-cell lung cancer.
A novel paradigm in tumor biology suggests that non-small-cell lung cancer (NSCLC) growth is driven by lung cancer stem cell (LCSC) like cells, but t here are still not any effective strategies to remove LCSCs. The bispecific antibody (BsAb) 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 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 of 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 antitumor effects of BsAb-5 were dependent on considerably suppressing T-regulatory cells (Tregs) and up-regulating effector T cells. On the basis of these results, we have identified a potential BsAb drug, which can effectively target c-MET and CTLA-4 in CD166+ LCSCs for the treatment of human NSCLC.
['Li|Jian-Feng|JF|', 'Niu|Yuan-Yuan|YY|', 'Xing|Yan-Li|YL|', 'Liu|Feng|F|']
D000818:Animals D018033:Antibodies, Bispecific D000074322:Antineoplastic Agents, Immunological D060908:CTLA-4 Antigen D002289:Carcinoma, Non-Small-Cell Lung D005260:Female D006801:Humans D008175:Lung Neoplasms D051379:Mice D008819:Mice, Nude D014411:Neoplastic Stem Cells D019859:Proto-Oncogene Proteins c-met D023041:Xenograft Model Antitumor Assays
c-MET CTLA-4 lung cancer stem cell-like cells bispecific antibody CD166 non-small cell lung cancer