This New Experimental Antibody Could Prevent Organ Rejection

An innovative designer antibody attracting attention as a potential treatment for Amyotrophic Lateral Sclerosis (ALS) has successfully prevented rejection of transplanted kidneys in non-human primates, giving the green light for testing in human organ recipients.

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If human clinical trials successfully prove its safety and effectiveness, the treatment could significantly improve the outlook for organ transplantation in the future.

"This less toxic approach has been pursued for over 20 years, and I think we are finally at a turning point," says immunologist and transplant surgeon Allan Kirk from Duke University.

"This could be a great advance for people in need of organ transplants."

For many patients with irreversible organ failure, organ transplantation is a lifesaving procedure. But the body's immune system frequently hinders the success of organ transplantation by identifying the transplanted organ as foreign and attacking it.

This immune response, known as organ rejection, can cause the transplanted organ to fail and, in extreme cases, cause death.

AT-1501, a monoclonal antibody, reduced rejection rates without increasing the need for immunosuppressive drugs or causing an increase in blood clots, which had been a side effect of a previous version of the treatment.

The study was funded in part by Eledon Pharmaceuticals, the company developing AT-1501 under the brand name Tegoprubart. The same drug has also shown promise in slowing progression of ALS in a phase 2a clinical trial completed last year. Demonstrating a similar effectiveness in organ recipients could provide a whole new approach in dampening their own immune responses.

"Current medications to prevent organ rejection are good overall, but they have a lot of side effects," says surgeon-scientist Imran Anwar from Duke University.

"These therapies suppress the immune system, putting patients at risk of infections and organ damage, and many cause non-immune complications such as diabetes and high blood pressure."

Monoclonal antibodies like AT-1501 are designed to act like human antibodies by cloning a single type of immune cell. AT-1501 targets a specific protein called CD40 ligand on the surface of some T cells, a type of white blood cell involved in the immune response.

AT-1501 works like an antibody against activation of T cells by binding to CD40 ligand. Inhibiting T cell activation in this way helps prevent multiple immune and inflammatory responses that contribute to rejecting the transplanted organ.

AT-1501 was tested for safety and effectiveness in kidney transplants in rhesus macaques and pancreatic islet transplants in cynomolgus monkeys. As tissues responsible for producing the body's insulin, Islet cell transplants have recently been approved by the FDA to treat type 1 diabetes.

The animals given AT-1501 after transplant treatments had fewer complications like weight-loss or reactivation of the latent virus cytomegalovirus, often seen after conventional immune system suppression treatments.

"These data support AT-1501 as a safe and effective agent to promote both islet and kidney transplant survival and function and allow us to advance into clinical trials right away," says Kirk.

AT-1501 is expected to be used in combination with existing immunosuppressive agents that target other aspects of the immune response, as is the current standard of care in kidney and islet transplantation.

"The push over the last decades has been to develop new, less toxic drugs," Anwar says. "We are hopeful this antibody moves us closer to that goal."

The study has been published in Science Translational Medicine.

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