After an organ transplant, the recipient’s immune system is suppressed with medication so that it does not reject the new organ. However, the current remedies have serious side effects. Researchers have now developed a new monoclonal antibody that specifically prevents rejection but has fewer side effects. Initial tests on primates were successful. Further studies will show whether the antibody is suitable for use in humans.
Organ transplants are only possible if the naturally occurring rejection reaction of the immune system is suppressed. Otherwise, it would identify the new organ as foreign and initiate an inflammatory response that damages the organ so severely that it becomes unusable. “Current drugs for preventing organ rejection are good overall, but they have many side effects,” explains Imran Anwar of Duke University in Durham. “These therapies suppress the immune system and put patients at risk of infections and organ damage. Many also cause non-immune complications such as diabetes and high blood pressure.”
First attempts failed
In the search for alternatives with fewer side effects, researchers are focusing on specific key points of the immune system. One of these is the receptor CD40, which is located on the antigen-presenting cells. These cells have the ability to pick up specific protein characteristics from pathogens or other non-self cells and “show” them to T cells and other immune system actors for recognition. When exposed to such an antigen-presenting cell, activated T cells bind to this receptor using a protein called CD40 ligand, initiating a rejection and inflammatory response.
Researchers have previously tried to block this ligand with the help of monoclonal antibodies and thus prevent transplanted organs from being rejected. In fact, one of these antibodies had proven so successful in pre-clinical studies that it had already been tested on human subjects. However, the clinical studies had to be stopped because many human test subjects developed thrombosis. The reason for this was that the antibody also bound to another target, the so-called Fc-gamma receptor on the blood platelets. In this way, it promoted the formation of blood clots.
Promising results in macaques
Anwar and his team have now modified the antibody in such a way that it continues to act against the CD40 lingand but no longer binds to the Fc-gamma receptor. They gave the newly designed antibody the name AT-1501. “We developed AT-1501 with the aim of avoiding the risk of thrombosis,” the researchers write. After they had first demonstrated in the laboratory that the new antibody actually only has the desired and not the undesired binding properties, they tested it on living primates. For the experiments, they performed a kidney transplant on four macaques and then treated them with AT-1501.
The result: “The AT-1501 infusions were well tolerated and no undesirable side effects were found, including no complications with thrombosis,” reports the team. One of the four monkeys had to be euthanized 56 days after the transplant because of a rejection reaction. However, the remaining three animals survived to the study endpoint three months post-transplant and showed minimal signs of an inflammatory response. After three months, the animals were killed to closely examine the transplanted organ. “In fact, the tissue examination showed no signs of a rejection reaction,” report the researchers.
Ready for human studies
Anwar and his team achieved similarly promising results in another group of macaques, into which they transplanted pancreatic islet cells. Here, AT-1501 alone could not prevent rejection, but it could in combination with common immunosuppressants. Compared to treatment with immunosuppressants without AT-1501, the new monoclonal antibody also improved the functionality of the transplanted islet cells. Side effects were less common than in the control group.
“These data demonstrate that AT-1501 is a safe and effective agent to promote islet and kidney transplant survival and function. This allows us to jump straight into clinical trials,” says Anwar’s colleague Allan Kirk. “This less toxic approach has been around for over 20 years and I think we’re finally at a tipping point. This could be a major advance for people who need an organ transplant.” The prerequisite for this is that AT-1501 also proves to be effective in human studies and does not cause any previously undetected serious side effects.
Source: Imran Anwar (Duke University School of Medicine, Durham, USA) et al., Science Translational Medicine, doi: 10.1126/scitranslmed.adf6376