The inhibition of angiogenesis to reduce tumour progression has shown promise, but the short half-life and high production costs of endogenous angiogenesis inhibitors, such as angiostatin, have hindered clinical development. Lars Holmgren et al. now report that vaccination with DNA that encodes the angiostatin receptor, angiomotin, overcomes these problems and those of developing active immunotherapies by breaking immune tolerance and provoking an immune response against angiogenesis. In addition, the angiomotin vaccine inhibited tumour progression in mice when given in combination with a tumour-cell-targeted DNA vaccine.

The authors used cDNA that encodes the human p80 isoform of angiomotin inserted into a plasmid vector (pcDNA3–Amot), and showed that transfection into the cervical cancer cell line, HeLa, led to expression of the angiomotin protein. Intramuscular injection and electroporation with pcDNA3–Amot into mice that were then challenged by the injection of mouse breast cancer cells led to the prolonged suppression of tumour growth compared with the injection of a control vector.

Next, the BALB-NeuT transgenic breast cancer mouse model (which is positive for rat epidermal growth-factor-receptor 2 (ERBB2, also known as HER2)) was used to investigate the ability of angiomotin to inhibit the angiogenic switch and tumour progression. The mice were vaccinated either before or after the onset of tumour angiogenesis, and although no effect on tumour progression was seen, vaccination reduced tumour angiogenesis by over 60%. Importantly, pcDNA3–Amot vaccination did not negatively affect the vasculature of the surrounding stroma or the vessels in mice retinas. When pcDNA3–Amot vaccination was combined with a DNA vaccine against ERBB2, 80% of treated mice were tumour free for more than 70 weeks — the ERBB2 vaccination alone delayed tumour growth but progression resumed.

So, what is the mechanism of the anti-angiogenic effect of pcDNA3–Amot? The anti-tumour effect was abrogated in mice that were treated with anti-CD4 antibodies to deplete CD4+ T cells. Furthermore, tumour growth was not inhibited when mice that lacked B cells (which produce antibodies) and antibody μ-chains were vaccinated. Sera harvested from vaccinated mice contained antibodies against angiomotin. Purified immunoglobulin completely blocked migration stimulated by basic fibroblast growth factor or vascular endothelial growth factor in angiomotin-transfected mouse aortic endothelial cells. These results confirm that production of anti-angiomotin antibodies is key to the anti-angiogenic effect of pcDNA3–Amot.

This approach to inhibiting angiogenesis overcomes problems commonly seen with other angiogenesis inhibitors and immunotherapies. Further investigation of angiomotin DNA vaccination, or anti-angiomotin antibodies, in combination with a tumour-targeted agent is warranted.