Benefits
Very high anti-cancer cell potency
0.1 - 10 femtomolar concentrations
Very low potency in non-cancer cells
100 to 1000 fold therapeutic indices
Broad spectrum anti-cancer activity
including colorectal, primary hepatic and ovarian cancers
A unique cancer killing mechanism
is active against drug resistant cancers
Excellent human serum stability
can be administered intra-vascularly
Self-amplifies in cancer metastases
maximized anticancer activity with minimized side effects
Originally developed in collaboration with Bayer Schering, ColoAd1 is our lead candidate using the directed evolution process and is now in late pre-clinical development and is currently undergoing GMP scale up production.
Directed evolution of oncolytic viruses
Unlike previous "rationally" designed oncolytic viruses, which used recombinant techniques to modify wild type viruses with various insertions and deletions, PsiOxus has used the power of natural selection to generate an entirely novel virus with optimised cancer-lytic properties.
This patent protected process of directed evolution is summarised below
1. Firstly, a chimeric adenovirus library was created by homologous recombination under atypical conditions of super-infection. ColoAd1 is a PsiOxus hybrid of Ad3 and Ad11p
2. Multiple rounds of selection then identified those chimeric viruses with a tumour dependent phenotype that also rapidly killed tumour cells. ColoAd1 rapidly replicates in cancer cells, causing them to burst.
3. The potent oncolytic viruses were then screened on normal cells to elect one with a very high therapeutic index. ColoAd1 has changes rendering it unable to replicate in normal cells.
Oncolytic viruses
Oncolytic viruses selectively propagate inside cancer cells, causing them to die by membrane disruptive 'lysis'.
For each cancer cell infected, an oncolytic virus can produce thousands of copies of itself that then spread to nearby cancer cells and kill them too. This represents a new generation of 'self-amplifying' cancer therapies.
So why doesn't ColoAd1 kill normal cells as well? The answer lies in the same changes which made it a potent anti-cancer agent. Having been evolved on cancer cells, ColoAd1 is no longer able to wrestle control over normal cells and cannot override cellular defence mechanisms. Interestingly cancer cells, by their very nature, need to turn off several basic cellular functions that would normally defend cells against viruses. For example, cancer cells are often deficient in apoptosis (a defence mechanism that causes cells to die in the event of virus infection). They also subvert the immune response around the cancer in order to prevent rejection. Under these conditions ColoAd1 can flourish, but is unable to spread outside of the permissive tumour environment.
ColoAd1 data
Creating new anticancer agents with improved selectivity for tumor cells compared to current therapies is one of the fundamental drivers of modern cancer research. ColoAd1 is highly selective for killing cancer cells and shows little or no activity on normal tissue. In a direct cell killing assay ColoAd1 demonstrates over 1200-fold more effective killing of human cancer cells than of human endothelial cells. Standard chemotherapy agents are much less selective for cancer cells, accounting for the severe side effects observed in the clinics. Irinotecan is a topoisomerase I inhibitor and one of the best chemotherapeutic agents available, yet it shows little selectivity for killing cancer cells over proliferating normal endothelium when compared with ColoAd1.
Measuring the ability of drugs to kill cells: In the laboratory, cell killing can be measured using a technique called the MTS assay that determines the number of viable cells at chosen point in time after exposure to a drug. The concentration of drug that kills half of the cells under these conditions is called the IC50 and this can be used to compare the potency of drugs with each other and on different cells.
Market potential
The initial target indications for ColoAd1 are metastatic colorectal cancer and primary hepatic cellular carcinoma. These are both exceptionally large market segments with significant unmet medical need.
Metastatic colorectal cancer
- The incidence of colorectal cancer is forecast to reach over 490,000 cases in the 7 major markets by 2018
- Over 50% of these patients will develop liver metastases
Primary hepatic cellular carcinoma
- Is the third leading cause of cancer mortality worldwide
- There is significant unmet medical need with few effective treatment options
- Market projections have exceeded $1 billion p.a.
