Using Tegoprubart to Support Genetically Modified Xenotransplant
David-Alexandre Gros, MD, the chief executive officer of Eledon Pharmaceuticals, discussed the company’s investigational monoclonal antibody and its use along with EGenesis porcine kidney transplant product.
This is the second part of an interview with David-Alexandre Gros, MD. For the first part, click here.
David-Alexandre C. Gros, MD
Credit: Eledon
EGenesis's EGEN-2784 is a porcine kidney that features a number of genetic modifications intended to prevent rejection in human patients, and is under evaluation for the treatment of end-stage kidney disease alongside the use of Eledon Pharmaceuticals’ tegoprubart, an investigational monoclonal antibody intended to improve the efficacy and safety of kidney transplants. Following the announcement of that the transplant of an EGEN-2784 kidney had been completed in a second human patient CGTLive® reached out to David-Alexandre C. Gros, MD, Eledon’s chief executive officer, to get his insight on the news.
Gros spoke about how tegoprubart differs from traditional approaches to immunosuppression and explained how it works. He emphasized the importance of turning white blood cells into T-regulatory cells rather than simply killing off the white blood cells.
CGTLive: Can you discuss the role of tegoprubart in kidney xenotransplant?
David-Alexandre C. Gros, MD: The role of tegoprubart is similar—but its mechanism is different—from today's typical cornerstone standard of care immunosuppression, which I mentioned is calcineurin inhibitor tacrolimus. It's similar in that its role is to protect the organ from the immune system. Our immune system has evolved over millions of years to recognize something that is foreign in our body from oneself—when that doesn't go right, that's called an autoimmune disease—but our immune system is very good at doing that. Typically, it can detect a single bacteria or single virus floating in our blood.
Now the challenge here, when we talk about organ transplantation, is we're putting in billions of cells that are by definition foreign because they're coming from another individual, and if we talk about xenotransplantation they're coming from another species, and so the immune system will immediately react and and attack that organ if it is not modulated or suppressed in some manner. This isn't new. We've known about this for hundreds, if not thousands, of years. Definitely going back to the Middle Ages, people had tried to transplant hands and noses, and of course, those transplants never worked because they weren't immunosuppressing and so the immune system would immediately attack those appendages.
Now, traditionally, the approach that's been used in transplantation has been to wipe out whole populations of white blood cells. Tegoprubart takes a very different approach. We are changing how white blood cells talk to one another. There are a few primary types of immune cells, they include a type of cells called the antigen-presenting cells. These are different types of cells that collect proteins or sugars in various different ways, and they present what are called antigens to the T-cells of the immune system. The T-cells in a certain way are the police officers of the immune system and when those antigen-presenting cells present the antigens to the T-cells, the T-cells can do 1 of 2 things. They either recognize that antigen as being foreign, in which case, they activate themselves, they polarize themselves, they turn themselves on, and the T-cells then become either killer T-cells, which do exactly what it sounds like (they attack and destroy cells that are expressing that antigen) or they become something called helper T-cells. It's the helper T-cells that in turn, activate the third type of cell in the immune system, which is a B-cell, and those are the cells that manufacture antibodies. So if the T-cells recognize an antigen as foreign, they turn on, activate the immune system, right? You're putting the foot on the proverbial gas pedal. The T-cells can go and attack themselves or they can get the B-cells to make antibodies to help mount an immune attack.
The second role of the T-cells is actually the opposite. If the T-cells determine that the antigen is self, and there's an immune attack going on, the T-cells can become T-regulatory cells, and those T-regulatory cells are the brakes of the immune system. Now what tegoprubart does is it inhibits or changes how the T-cells communicate with both the antigen-presenting cells and the B-cells. By doing so, it stops the T-cells from becoming either killer or helper T-cells. It also, as a result, inhibits the B-cells from becoming activated and hence generating antibodies. In that way, it's taking the foot off the gas, and it doesn't kill the T-cells, but it helps induce them to become T-regulatory cells, and in that way, tone down the immune reaction that's happening.
This is really a very modern approach, a very targeted approach, to immunomodulation. We're no longer talking about wiping out whole white blood cell populations in order to control the immune system. What we're doing is truly changing how the immune system communicates so that it doesn't mount an attack on the transplanted organ.
