Angiolix® Fact Sheet

What is Angiolix?

Angiolix (HuMc3) is a humanized monoclonal antibody which has considerable potential for the treatment of cancer, particularly breast and ovarian, through its affinity for a novel target, Lactadherin. Angiolix is currently in preclinical development.

What is Lactadherin?

Lactadherin is a 46kDa extracellular matrix protein that appears to be released by numerous types of tumor cells, including most breast cancers and ovarian cancer. Lactadherin has a critical role in promoting the growth of new blood vessels to support tumor growth through activation of VEGF-mediated angiogenesis. Access Pharmaceuticals has exclusivity to therapies that target this protein for cancer treatment. Therefore, any other product targeting Lactadherin for the treatment of cancer cannot be developed without a sub-license from Access.

Mode of Action of Angiolix

Angiolix is a monoclonal antibody which interrupts VEGF-mediated angiogenesis in tumors; a process which stops new blood vessels forming, and hence starves the growing tumor of oxygen and nutrients. The market for anti-angiogenesis factors represents a $1 billion + opportunity currently occupied by VEGF inhibitors such as Avastin. Through its binding to Lactadherin, Angiolix is anti-angiogenic by interrupting a process ‘upstream’ in the VEGF-cascade to that of Avastin. It therefore has the potential to be even more successful in promoting anti-angiogenesis.

In Vitro Data

The ability of Angiolix to bind to Lactadherin has been shown by several methods including ELISA assay (see below), native western blots of human cream samples, and immunoprecipitation with protein-A sepharose.

Angiolix® has been shown to bind to MX-1 breast epithelial tumor tissue as well as an ovarian tumor line SKOV3, which is known to express high levels of Lactadherin.

In Vivo Data

The following two graphs were generated from studies of Angiolix in mice bearing human MX-1 tumor xenografts. The graphs on the left shows that tumors grew faster when the mice were either untreated, or treated with a monoclonal antibody that has no affinity for Lactadherin. There is a significant drop in the rate of tumor growth when the mice were treated with Angiolix.

For the study which generated the data shown in the graph on the right, the radioisotope yttrium-90 (which is commonly used for radioimmunotherapy of cancer) was bound to Angiolix. The tumor is now attacked in two ways because of the binding of Angiolix to Lactadherin which is released by the tumor:

• by the inherent anti-tumor activity of Angiolix, and

• the targeted delivery of radioactivity to the tumor.

Several animals were cured as a result of this therapy.

Why Angiolix May Attack Cancer Stem Cells

Recent work has indicated a role of cancer stem cells (CSC’s) in initiation and propagation of several types of cancer. CSC’s may also be the cause of long term resistance to many conventional therapies. This property has been attributed to the ability of CSC’s to both provide new stem cells (self renewal) and highly proliferative cells. Although the daughter cells are themselves subject to destruction by therapies which target rapidly dividing cells, the stem cells are not susceptible to these therapies and remain active even after the therapies have resulted in tumor shrinkage. The reason for tumor recurrence has therefore been proposed to be due to the ability of the remaining stem cells to divide.

The self renewal of CSC’s has been indicated to require vasculature growth and to be inhibited with anti-angiogenic therapies including inhibitors of the VEGF pathway. By inhibiting VEGF-mediated angiogenesis, Angiolix® may not only halt growth of the rapidly dividing cell population by preventing the supply of new vasculature, but also prevent the recurrence of new tumors by inhibiting growth of the cancer stem cells.

Summary

Angiolix is a humanized monoclonal antibody, currently in preclinical development, that has a similar effect on tumors as the highly successful anti-angiogenesis drug, Avastin. Angiolix has the potential to be superior to Avastin as it impacts tumor angiogensis at a point more critical to the angiogenic process - binding to the Lactadherin protein. Lactadherin has been shown to be released by most breast cancer tumor cells. In addition there is also a growing body of evidence that it may be implicated in the angiogenesis process of other types of cancer, such as ovarian and colorectal. Therefore, Angiolix is a proprietary Access product that has great potential for the treatment of breast cancer and possibly other cancers.