Background: GS-5745 (Andecaliximab) is a monoclonal antibody that selectively inhibits matrix metalloproteinase 9 (MMP9), enabling investigation of the physiological functions of this protease.
Results: Pro-MMP9 was elevated in serum and tissue from patients with gastric cancer (serum MMP9 p<0.0001 vs healthy control). Active MMP9 was higher in gastric tumors (p=0.001) as compared to normal tissue. IHC revealed that pro-MMP9 was primarily expressed by infiltrating myeloid cells, and secondarily by tumor epithelial cells. MMP9 inhibition reduced tumor growth in the orthotopic HCT-116 mouse xenograft model (p = p<0.0001), and fibrillar collagen adjacent to the tumor nodule (second harmonic microscopy, p=0.0172). MMP9 inhibition also reduced tumor growth in the orthotopic HC11-NeuT syngeneic tumor model (p = 0.0005). Immunophenotyping showed that anti-MMP9 and anti-PDL1 co-treatment promoted a 2.8-fold increase in CD3+ cells in tumors (p=0.01), which was associated with a 3.2-fold increase in CD4+ T cells (p=0.006) and 2.8-fold increase in CD8+ T cells (p=0.013) concomitant with a decrease in tumor-associated CD25+ FoxP3+ regulatory T cells (p = 0.04). In vitro, MMP9 directly proteolyzed CXCR3 chemokines, including CXCL9/10/11. In a gastric cancer Phase I trial of GS-5745 in combination with chemotherapy, the majority of patients experienced either a partial or complete response.
Conclusion: MMP9 is a novel target in oncology, and Andecaliximab is currently in a Phase II/III trial for gastric cancer.