Developing Bispecific Heterodimer that Binds Both MMP9/14 and IL-17 for Cancer Therapy

The binding of at least two molecular targets with one single bispecific protein is an attractive therapeutic concept for oncology drug development. Different cell signaling pathways in cancer are interconnected and complementary and can result in biological redundancies, thus, bi-specific proteins that can interfere with these different pathways and act on multiple cancer targets can have additive or synergistic effects. In this research, we generated a bi-specific heterodimer that targets and inhibits two such targets, namely matrix metalloproteinase-9 and -14 and the immune system modulator, IL-17, both involved in essential process for angiogenesis and cancer metastasis. MMPs are enzymes that capable of degrading essentially all components of the extracellular matrix (ECM). IL-17, a widely recognized inflammatory cytokine, expression has been detected in several human tumours including prostate, breast and gastric cancer. In addition, IL-17 has been shown to promote invasiveness in breast cancer and gastric cancer. Our approach will thus lead to a new generation of cancer inhibitors that are based on dual targeting of inflammatory and extracellular matrix (ECM) remodeling pathways.

In this project, we developed a bi-specific heterodimer that simultaneously targets both MMP9/14 and IL-17. To achieve this goal, we designed a fusion construct with the two proteins, N-terminal regions of TIMP2 and soluble IL-17A receptor, conjugated. TIMP2 is a natural inhibitor of MMPs and IL-17A is the ligand of IL-17A receptor. The bi-specific heterodimers were expressed in mammalian cells and purified as soluble proteins. We were able to show that these heterodimers bind and inhibit both targets in vitro and in cell-based experiments. We also show that the bispecific proteins inhibit cancer invasion in different cellular.