Pluristem's IP strategy: great expectations

Several years after scientists found a way to harvest stem cells efficiently from the placenta after birth, companies are turning to it increasingly as a source for cell-based therapies.

The organ that for nine months keeps both mother and baby healthy during pregnancy and which, further research suggests, also plays a role in their long-term health, is a rich source of stem cells.

However, so understudied is the placenta that the Maryland-based Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH) has announced a Human Placenta Project, an initiative aimed at “unlocking the secrets” of the one-pound (500g) organ.

The NIH hopes that the project will create a greater understanding of the placenta’s structure, development and function. Meanwhile, one company in Israel is using the placenta’s potential to develop novel therapies for the treatment of cardiovascular diseases and pre-eclampsia.

Pluristem Therapeuticas extracts cells from donated placentas and cultures them using a proprietary technology to create its patented PLX, or ‘placental expanded’ cells, a drug delivery platform that releases therapeutic proteins in response to different inflammatory diseases.

As Zami Aberman, chairman and chief executive of Pluristem, explains, placental cells’ unique position as an intermediary between mother and baby means they’re less likely to be rejected by the body after administration.

“In nature, the placenta is a place where the mother and the baby are communicating,” he says. “Even though they have separate immunological systems, they are not attacking each other.”

Aberman continues: “PLX cells have been injected into patients in clinical studies two weeks apart, or three months apart, from the same donor, without an immune reaction, which cannot be achieved by other cells.”

Pluristem cultures its cells using a 3D scaffold, as opposed to plastic 2D plates, which can make the cells behave a certain way. “When they reach confluence on a 2D plate they send signals to stop growing,” Aberman says.

“We’re generating a 3D micro-environment for the cells that is completely different from the 2D,” Aberman explains.

“To the cells it’s a human-like micro-environment.”

He continues: “The 3D cell-to-cell communication and the controlled culture environment in the bio-reactor enable us to achieve different gene expressions that allow us to generate the required secretion profiles for specific therapeutics.”

What Pluristem gets are off-the-shelf cells that can help heal damaged tissue, such as muscle, help tendon injuries and repair rotator cuffs.

Conception

Pluristem acquired the basic IP on the 3D culturing technology from the Weizmann Institute of Science and the Technion–Israel Institute of Technology in 2007.

Aberman explains that Pluristem had discovered a few years before then the importance of culturing conditions in cell therapy.

“Tiny changes in the culturing process, such as the pH levels, can generate an epigenetic change in the cell. That led us to the decision that we had to develop a manufacturing tool that would allow us to do the manufacturing in precisely the same condition every time.”

From its initial IP, the company developed a variety of technologies to control the manufacturing so that it would yield the same cells every time, and found ways of changing cell properties by altering the culture conditions, creating opportunities for creating new IP.

Protection

There are four levels of IP protection, Aberman explains. “The first level of protection is the 3D culturing. As a result of the 3D culturing, the cultured cells are different from cells grown on a 2D plate, generating a unique composition of cells.

“We generated a unique, proprietary composition of matter due to the 3D scaffold, which is the second layer of protection.”“Our innovation is to take cells from nature and grow them on the 3D scaffold, which generates a change in the cell that can be analysed in the gene profile expression.

The third layer is the therapeutic use of the cells, and the final layer is the equipment Pluristem developed to manufacture the cells.

“You have different levels of protection and you apply them as needed based on the infringement of the patent,” Aberman says.

Pluristem currently holds 30 patents, many of which cover cultured placental cells and the methods for culturing them, which have been issued by the US, EU, and countries including China, Russia and South Africa. It has 120 applications pending.

Aberman says that the company’s strategy is to start filing in the US, then make a decision as to where else to file based on the therapy’s target.

“Usually we’ll file our patents in the US, Europe, Japan, Korea and Australia, and sometimes in Russia, South Africa and South America—it depends,” he says.

Pluristem also has a number of trade secrets, mainly to protect the manufacturing processes. Patents protect the definition of 3D culturing, and the general culturing condition, but the processes that provide greater stability in the cultured cells are protected by trade secrets, Aberman explains.

The field is ripe for creating new IP, too. “Every year we file two to six new patent families, so it’s growing all the time,” he says.

At the moment, Pluristem is working with the Charité university hospital in Berlin to develop new products, and has licensing agreements with a range of different companies that develop Pluristem products for specific indications.

“When we start developing the project, the cells are perfected by our 3D culturing,” says Aberman.

“For example, our first partner was United Therapeutics. We out-license them the marketing rights to the cells for pulmonary hypertension, while we keep the IP and the manufacturing rights, which isn’t common in this area,” Aberman says.

So far, Pluristem does not have any approved products, but it is currently conducting Phase II clinical trials for critical limb ischaemia (the sudden loss of blood flow to a limb), intermittent claudication, and muscle injury.

One of its product lines, focused on the area of pulmonary hypertension, is licensed to United Therapeutics Corporation, based in Maryland.

Long term

Pluristem’s goal is to receive a biologic licence application for one of its products.

“We assume our first approved product will be for an indication of severe pre-eclampsia or bone marrow transplant failures,” he says.

He says that Pluristem hopes to take advantage of the adaptive licensing provision in Europe, and the breakthrough therapy designation in the US, which allow drug makers to enter the market with their much-needed therapies faster.

“That’s very important to us as a public company,” Aberman says.

His aim is to “tune” the cells so they can be used for specific indications, as is being done with antibodies. “Just as there are antibodies for specific indications, we will have cell types for specific indications and specific fields.

“By using the 3D technology we can tune the cells’ secretion properties, and ten years down the road the world will understand that the source of the cells is important, but the culturing is more so, and we’ll have many products on the market.”

With the NIH’s efforts to promote understanding of the placenta, we could be on the brink of a new era of discovery.