Red Blood Cells: Ready For Double-Duty?

RED BLOOD CELLS: READY FOR DOUBLE-DUTY?

Biotech Primer WEEKLY talks a lot about white blood cells, with good reason. These powerful immune cells defend us against pathogens and have recently been adapted to fight cancer as CAR-T cells. What about the body’s other major type of blood cell–red blood cells (RBCs)? Although they receive less media attention, scientists have long recognized these cells’ critical importance in supplying oxygen to the body.  Now drug companies are hoping to tap RBCs’ potential to transport drugs as well. This WEEKLY explains how.

RBCs have a few features that make them ideal for delivering drugs:

• Stability: These cells live for up to three to four months.
• Biodegradability: After a few months in circulation, RBCs are naturally broken down in the spleen and liver and excreted by the kidneys.
• Immune System Tolerance: Assuming a compatible donor, red blood cells don’t provoke an immune response, significantly reducing the chance of the patient’s body rejecting the product. Red blood cells from universal donors– O- and Rh-negative – may serve as a starting point for “off-the-shelf” therapies. These can be prepared in advance for multiple patients, rather than custom-made for each patient.

Given these characteristics, how do researchers turn red blood cells into drug delivery systems?

• Attachment: Fixing therapeutic proteins, small molecule drugs, or nanoparticles to a cell’s surface creates “carrier RBCs.” In this approach, drugs are chemically linked to the RBC or attached to antibodies that then bind to the RBC surface.
• “Loading” red blood cells: Researchers place the cells in a solution with a lower concentration of salts and other materials than that of the red blood cell. The difference in concentration causes water to move into the cell. As the water moves into the RBC, transient pores are created, through which the therapeutic cargo enters.
• Genetic engineering: Here, researchers modify RBCs to contain a gene that codes for a therapeutic protein, which the cells then produce.

The Rosy Future Of RBC Therapies

While there aren’t any RBC therapeutics on the market now, a few are in clinical development:

• Erydel (Urbino, Italy) is developing a treatment platform call EryDex System is which RBCs are loaded up with a drug and infused into patients. The drug slowly diffuses out of the RBCs over an extended period of time. The loaded-up cells are referred to as EryDex System End Product (EDS-EP). An EDS-EP loaded with dexamethasone sodium phosphate, an anti-inflammatory steroid drug, is in Phase III clinical testing for the rare inherited disorder ataxia-telangiectasia. Previous studies suggest that this drug improves neurological symptoms in patients.
• ERYtech Pharma (Lyon, France) has developed the ERYCAPS RBC-based delivery platform, which, like EryDel, is based on hypotonic loading of therapeutic agents. Their lead product, Eryaspase, consists of RBCs carrying an enzyme called L-asparaginase for treating cancer. How does it work? L-aspariginase breaks down the amino acid asparagine. Healthy cells can synthesize this amino acid, whereas many types of cancer cells can’t. By encapsulating the enzyme in long-lived RBCs, it stays in circulation long enough to degrade available asparagine. This “starves” the cancer cells that can’t make it themselves. Eryaspase is now in Phase III clinical studies for acute lymphoblastic leukemia and in Phase II for acute myeloid leukemia and pancreatic cancer.

The Next Big Thing In Immunotherapy?

One of the most interesting areas of preclinical development for RBC therapeutics is immunotherapy:

• Cancer: Rubius Therapeutics (Cambridge, MA) is genetically engineering RBCs to display proteins on their surface that can activate killer T-cells to destroy tumors.
• Autoimmune disease: By activating a different type of T-cell, regulatory T-cells, researchers are hoping to defeat autoimmune diseases, including Type 1 diabetes. The immune systems of patients with this illness attack the insulin-producing cells of the pancreas. Scientists at Anokion (Lausanne, Switzerland) are developing a platform that involves attaching portions of “autoantigens” – proteins in patients’ bodies that induce autoimmunity – to the surface of RBC. This “trains” the patient’s immune system not to respond to his or her insulin-producing cells. Rubius is also working on genetically-engineered RBCs to induce immune tolerance.

Cell therapies such as red blood cell therapies, CAR-T therapies and stem cell therapies are classified as either allogenic or autologous. Autologous cells come from the patient’s own body. An example is current CAR-T therapies, in which white blood cells are removed from the patient, modified in the lab to be tumor-seeking, and infused back into the patient. The advantage of using autologous therapies is there is essentially no risk of immune system rejection, since the cells come from the patient’ own body. The downside? They are more expensive and time-consuming to produce than allogenic therapies, which are derived from cells that come from a compatible donor and are not patient-specific. Many of the RBC therapies being tested are allogenic. Scientists are working on developing allogenic CAR-T therapies.