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ColoAd1

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, ovarian and other common solid tumours

A unique cancer killing mechanism
is active against drug resistant cancers and cancer stem cells

Excellent stability in human blood and ascites fluid
can be delivered by intra-vascular and intra-abdominal delivery

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.

The Evolve Clinical Study

The Evolve study is the first time that ColoAd1 is being tested in human patients. Click Here for more information.

Directed evolution of oncolytic vaccines

Unlike previous "rationally" designed oncolytic vaccines, 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

See Figure 1.

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 vaccines 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 vaccines

Oncolytic vaccines selectively propagate inside cancer cells, causing them to die by membrane disruptive 'lysis'.

See Video.

For each cancer cell infected, an oncolytic vaccine 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.

See Figure 2.

As a replicating virus, ColoAd1 amplifies at the site of action, with each cell producing thousands of viral copies that can go on to spread within and kill neighbouring cancer cells.

See Figure 3.

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.

ColoAd1

ColoAd1 Benefits »
The Evolve Clinical Study »
Directed evolution of oncolytic vaccine »
Oncolytic vaccine »
ColoAd1 data »
Market potential »
Key publications »


Figure 1.
ColoAd1


Video. A summary animation illustrating how ColoAd1 targets cancer cells. Please note, the exact details surrounding the ColoAd1 Mechanism of Action are currently the subject of on-going investigation.


Video. The cells in this video are metastatic drug resistant tumour cells, derived from a patient with ovarian cancer (SKOV3 cells). At the start of the video, the cells are in vigorous motion and at this early stage there is no sign that they have been infected with a small number of ColoAd1 vaccine particles (the inoculation dose was at a ratio of six virus particles per cancer cell). As time passes, the cells become more granular and slow down, eventually they are destroyed from within. The final few seconds of the sequence shows disrupted cell carcasses and debris from the once living cancer cells. All of the tumour cells in the vessel have been killed and the total time elapsed was 83 hours. This video was taken using a culture chamber deigned by David Barlow.

Figure 2.
ColoAd1

Figure 3.
ColoAd1

ColoAd1 production 'factories' within the nucleus (uniform icosahedral particles) of a human lung cancer cell (A549 cell) 72 hrs after infection with ColoAd1.

Key Publications

[1] Kuhn I, Harden P, Bauzon M, Chartier C, Nye J, Thorne S, Reid T, Ni S, Lieber A, Fisher K, Seymour L, Rubanyi GM, Harkins RN, Hermiston TW. Directed evolution generates a novel oncolytic virus for the treatment of colon cancer.. PLoS ONE 2008; 3 (6):e2409.