A novel bispecific c-MET/PD-1 antibody with therapeutic potential in solid cancer

Abstract

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 bispecific antibody (BsAb) that can bind cellular-mesenchymal to epithelial transition factor (c-MET, overexpressed in several human solid tumor), and programmed death-1 (PD-1, involved in cancer cell immune evasion) with high affinity and specificity. We found that BsAb can induce the degradation of c-MET protein in cancer cells, including MKN45, a gastric cancer cell line, and A549, a lung cancer cell line. BsAb inhibited hepatocyte growth factor (HGF)-mediated proliferation, migration, and antiapoptosis, and downregulated HGF-stimulated phosphorylation of c-MET, protein kinase B (AKT), and extracellular signal-regulated kinase (ERK1/2). BsAb can also rescue T cell activation. Furthermore, xenograft analysis revealed that BsAb markedly inhibits the growth of subcutaneously implanted tumors and chronic inflammation. On the basis of these results, we have identified a potential bispecific drug, which can effectively target c-MET and PD-1 for the treatment of human solid cancers.

<p><em>MET</em> Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?</p>

“…Researchers have attempted MET inhibition as an immunologic stimulant, and a bi-specific MET/PD-1 dual-acting monoclonal antibody was created and tested with good pre-clinical results. 94 Moreover, NK1-targeted chimeric antigen receptors (CAR-T cell immunotherapy) were also developed to mediate MET-dependent T-cell activation against malignant cells. 95…”

HGF/MET and the Immune System: Relevance for Cancer Immunotherapy

“…Recently, some approaches are under development, including drug design and cell therapy. A novel dual inhibitor of MET and PD-1 was designed by Sun et al [ 83 ] and tested in multiple cancer cell-type models. It demonstrated a strong anti-proliferative and anti-metastatic effect in vitro and in vivo, and it reduced the production of inflammatory chemokines such as IL-6 and TNF-α, thus suggesting an important therapeutic potential, although still in the preclinical model stage [ 83 ].…”

Optimized Expression and Characterization of a Novel Fully Human Bispecific Single-Chain Diabody Targeting Vascular Endothelial Growth Factor165 and Programmed Death-1 in Pichia pastoris and Evaluation of Antitumor Activity In Vivo

“…Although both a syngeneic tumor model and an allogenetic tumor model can be used to assess immune checkpoint inhibitor activity, for the development of a therapeutic antibody drug, it is more convincing to evaluate the antitumor activity of immune checkpoint inhibitors using an immunodeficient mice model for human cancer. Additionally, a syngeneic tumor model might compromise the efficacy of immune checkpoint inhibitors due to low homologies between human PD-1 and mouse PD-1; therefore, we evaluated the BsDb’s antitumor activity in vivo using a PD-L1 positive HT29 colon cancer xenograft mouse model based on many previous studies [ 39 , 40 , 41 ]. VEGF antibody has prolonged the survival of patients with colon cancer when in combination with chemotherapy; however, clinical observations revealed the resistance to anti-angiogenic therapy in colorectal cancer was caused by various intrinsic or acquired mechanisms, including the immunosuppressive tumor microenvironment [ 42 ].…”