Cancer; ophthalmic disease

Cell culture and mouse studies suggest a SEMA3A-based fusion protein could help treat metastatic pancreatic cancer and AMD. The fusion protein consisted of the sema and plexin-semaphorin-integrin domains of mouse SEMA3A containing a point mutation (A106K) for enhanced binding to its receptor PLXNA4, linked to the Fc domain of mouse IgG1. In monkey fibroblast-based binding assays, the fusion protein bound PLXNA4 with a K_d of 0.7 nM. In a mouse model of metastatic pancreatic neuroendocrine cancer, the fusion protein decreased tumor growth, lymph node metastasis and markers of disease progression compared with vehicle. In an orthotopic mouse model of metastatic pancreatic ductal adenocarcinoma (PDAC), the fusion protein or the fusion protein encoded in an adeno-associated viral serotype 8 (AAV8) vector decreased primary tumor volume and metastatic burden in the liver compared with wild-type SEMA3A or empty vector, and the SEMA3A variant decreased markers of disease progression and increased survival compared with vehicle. Also in the model, the fusion protein plus gemcitabine decreased tumor growth and liver metastases compared with either agent alone. In a mouse model of AMD, intravitreal injection of the fusion protein decreased choroidal neovascular area compared with vehicle or wild-type SEMA3A. Next steps could include testing the fusion protein in additional cancer models...