Blocking the immune system aims to improve kidney transplants success rate

Irish biopharma company Opsona Therapeutics last week announced a new round of investment, to the tune of €33 million. Their goal? To dampen the body's early immune response to kidney transplant and so improve the odds that the transplanted organ will bed down safely in its new home.

If it works, it could make more organs useful for transplanting and help to address the enormous waiting list of people on dialysis, according to Prof Luke O’Neill, a co-founder, director and chief scientific officer at Opsona and professor of biochemistry at Trinity College Dublin.

So how can dampening the early immune response protect an incoming kidney? Opsona is targeting an acute immune response to the transplant called inflammation, explains Prof O’Neill.

Tolls on patrol

Your body has an “innate” immune system that includes cells whose job it is to pick up on signs of danger, such as an injury, and trigger a response called inflammation to help address it. One of these patrol cells is a type of white blood cell called a macrophage, and its outside surface is studded with sensor molecules called Toll-like receptor 2 (TLR-2).

When a protruding TLR-2 meets a molecule that tells it there is injured tissue around, the TLR-2 triggers the macrophage to ramp up and start inflammatory proceedings.

“TLR-2 is like a burglar alarm,” explains O’Neill. “The intruder in this case is tissue injury and the alarm goes off on the surface of these macrophages, which in turn triggers a reaction inside the macrophage and the cell starts to make proteins to wake up the immune system.”

In a kidney transplant, the alarm bells can sound early on, he notes.

“It happens very rapidly. The TLR-2 is there to sense danger, like tissue injury and get the immune system going to help to repair the injury,” explains O’Neill. “But that system can get out of control in a kidney transplant because if you put a kidney into someone’s body, it is very inflamed, it’s highly traumatised and the Toll-based system which senses danger goes into overdrive, which is not at all helpful.”

Dampening the immune response

Opsona’s approach is to block TLR-2 with their molecule, so that it can’t pick up on the signs of tissue injury. Studies in animal models suggest that blocking the TLR-2 molecule in this way could protect a transplanted kidney early on. “The TLR-2 molecule really seems to be an important one for kidneys,” says O’Neill.

Opsona has moved into clinical trials in healthy people and in transplant patients, which O’Neill says are progressing well, and they are ultimately looking at the possibility of improving transplant success with “marginal” kidneys.

“We are particularly focusing on the situation where they loosen up some of the criteria – maybe the kidney is slightly longer out of the donor, and perhaps slightly older donors are acceptable,” he says. “They are the transplants we are looking to protect because 40 per cent of those kidneys fail. Our goal is to bring that from 40 per cent to 20 per cent.

“If we can double the usefulness of these marginal kidneys, that will be a big clinical benefit because it could increase the number of kidneys that are available.”

Any potential treatment would be given as an “add-on” to existing treatment, he explains, and the hope is to get the kidney through the early post-transplant days without the inflammation response going into overdrive, explains O’Neill.

Transplantation is not the only situation where dampening down an innate immune response could be useful. “TLR-2 seems to play a key role in signalling in other diseases too, and we are now exploring where else our approach could be used,” says O’Neill.

Turning the immune system on cancer

A spin-out from Opsona, TriMod Therapeutics Ltd, is also looking to target the immune system in disease, this time to boost the body's own defences against cancer. The company spun out of Opsona in 2010 and is based on research carried out by Opsona co-founder Prof Kingston Mills in Trinity.

The idea is to change the balance of the immune system so the body can attack tumours more effectively, explains chief executive Dr Jeremy Skillington.

“A tumour can be very good at cloaking itself from the body’s natural defences, but we are decloaking the tumour and exposing it to an amped up immune system,” he says. “We have seen really good results in lung, melanoma and colorectal cancer in animal models, and the next step is to take that through to additional pre-clinical studies and human studies over the coming years.”

In 2011, TriMod announced it had secured seed funding of €750,000 from Enterprise Ireland, Opsona and Oyster Technology Investments Ltd, and the company is now looking for the next round.

“We are currently fundraising to transition into the clinic,” says Skillington. “Meanwhile I’m delighted for the good people at Opsona on their fundraising, they have a very promising product.”