果冻影院

CD25鈥檚 relaunch as a drug target was owed to experiments 鈥� done in Quezada鈥檚 and Peggs鈥檚 labs at聽果冻影院 Cancer Institute and supported by Cancer Research UK (CRUK) 鈥� that demonstrated the importance of a sub-set of T cells known as regulatory T cells in inhibiting immune responses to cancer cells. Quezada worked with CRUK to secure patents on the approach. Then, in 2016 he partnered with a small UK biotech called Tusk Therapeutics to develop a drug.

In an early meeting with Tusk, Quezada was asked if the antibody his team had used was the best he could provide? Taken aback, he replied: 鈥淲e spent 10 years figuring out this thing, and now you want something better?"

But this conversation sparked an insight that changed everything, ultimately leading to a drug that was instrumental in Roche paying up to $798 million to acquire Tusk in 2018. Reflecting on the work with Tusk, Quezada says, 鈥淚t was a delight 鈥� one of the best collaborations I鈥檝e ever had.鈥�

Redefining CD25

Quezada鈥檚 early work on CD25 was conducted in Jim Allison鈥檚 lab at Memorial Sloan-Kettering Cancer Centre in New York. The immunotherapy revolution unfolding there was founded on the fact that the human immune system normally destroys cancerous cells 鈥� but that as certain tumours grow and evolve, they start to evade immune surveillance.

Allison had shown how, as a tumour develops, mechanisms emerge which suppress a critical population of T cells, known as effectors, that normally recognise cancer cells and tag them for destruction. Some of the signals that inhibit T effectors in tumours act at checkpoint receptors 鈥� receptors that ordinarily function to keep any immune response proportionate to the need for them. And Allison鈥檚 demonstration that blocking these checkpoint receptors disinhibited T effectors, allowing them to destroy patients鈥� tumours,聽

Allison鈥檚 focus was T effector cells, their interaction with cancer cells and how this is regulated by checkpoint receptors. But Quezada was interested in a third player: regulatory T cells or Tregs. These T cells function to suppress T effectors and thus regulate immune responses. Quezada asked whether Tregs inhibiting T effectors within tumours are also critical for cancer cells escaping the immune system? Gradually, he convinced himself and Allison that this was an essential piece of the puzzle.

But an equally important legacy of his time in the Allison lab, was Quezada witnessing first-hand how the clinical success of checkpoint inhibitors was achieved by basic researchers and clinicians working in constant dialogue. 鈥淭hat's when I started seeing the power of taking basic research and being very smart on how you analyse its impact as it gets into the clinic,鈥� he says. 鈥淚 said, 鈥楾his is exactly what I want to be doing. I want to be working at this interface鈥�.鈥�

At this point, Karl Peggs, a clinical fellow with whom Quezada had worked with in Jim Allison鈥檚 New York lab, was instrumental in recruiting him to 果冻影院. Peggs had already moved to London and he told Quezada that if he moved to 果冻影院, he could plug a gap between clinical trials and basic immunology research. A grant from CRUK was instrumental in securing the position.聽

However, Quezada didn鈥檛 arrive at 果冻影院 with a specific drug in mind. 鈥淚 don't think that's how it works,鈥� he says. 鈥淭hese things are organic. It's like a little plant, they emerge.鈥�

A seed, however, had been planted in New York with the Treg work. The checkpoint inhibitors that had entered the clinic were thought to act by directly disinhibiting T effectors. But Quezada鈥檚 group 鈥� controversially 颅颅鈥� found evidence that these drugs could also deplete Tregs in tumours and that this was a vital part of their action.

Eureka moment

This reignited interest in CD25 because 鈥� unlike checkpoint receptors 鈥� it is expressed abundantly on Tregs and only at low levels on T effectors. Designed the right way, he and his group postulated, anti-CD25 antibodies might offer a way to powerfully and selectively deplete Tregs and liberate T effectors to attack cancer cells. Then came the moment the team had been dreaming of 鈥� they found their newly designed antibody caused a stronger immune response against the cells it bound to 鈥� which in turn caused tumours to shrink. 鈥淭hat was kind of the eureka!鈥� Quezada says.

Crucially, this antibody had antitumour effects when administered to mice after a cancer had grown. The idea for a drug, formed as a seed in Quezada鈥檚 mind in New York, had taken root in London.

Forming partnerships

Regular discussions of translational opportunities were a key part of Quezada鈥檚 CRUK fellowship, and soon after he鈥檇 grasped the potential of CD25, he and the charity explored ways to successfully file patents. The problem was, the earlier excitement around CD25 and the development of antibodies against it to treat graft versus host disease and T cell lymphomas, meant there were already many patents concerning CD25. In order to secure a patent, he and CRUK needed to demonstrate that their new antibody represented a genuinely novel invention.

While they worked on this, Tusk Therapeutics became excited by the CD25 data, and told Quezada if he could patent it, they would license it. CRUK and 果冻影院 redoubled their efforts and found a way to file IP and establish a collaboration with Tusk.

An essential element of this deal was a provision allowing Quezada鈥檚 lab to continue research on CD25 and anti-CD25 antibodies, allowing him to continue his academic career. He was delighted with the arrangement they reached. 鈥淭o me,鈥� he says, 鈥渋t was corporate drug development without having to leave my beautiful academic job.鈥�

Then, came the fateful meeting where Quezada was asked by Tusk if he could produce a better antibody.

The insight this question sparked came from considering CD25鈥檚 function. To date, Quezada had seen CD25 primarily as simply an antigen on Tregs, to which an antibody could bind to induce cell death. Because CD25 was expressed sparsely on T effectors, these cells were spared death.

But CD25 is more than just an antigen. It is the receptor for interleukin 2 (IL2), an important activator of T effectors, especially within the tumour microenvironment. Discussing this, everything suddenly fell into place. The antibody Quezada was using blocked CD25鈥檚 ability to function as a receptor for IL2. This meant that while it was depleting Tregs (thereby, disinhibiting T effectors), it was simultaneously limiting T effector activation by preventing them being stimulated by IL2.

Immediately, the lab set out to generate a new mouse antibody that would stick to CD25 without blocking IL2 signalling. Tested in mouse cancer models,聽聽And these results were right on time to tell Tusk to change the criteria by which they judged a candidate human antibody: it still had to bind CD25 and kill Tregs but, now, it had to also spare IL2 signalling.

The speed with which this all happened would have been impossible working solely as an academic, Quezada says. Throughout the project, the partners shared a will to move quickly, and this allowed them to optimise the division of work between Quezada鈥檚 and Tusk鈥檚 labs. As the partnership generated ever more promising data, Roche expressed an interest in acquiring Tusk.

Roche would take the drug though toxicological screening and into phase 1 clinical trials, while Quezada had the聽freedom to work with mouse antibodies in order to continue to drive the science underpinning this target. He also secured a relationship with Roche in which his team and Roche continue to investigate the mode of action of anti-CD25 antibodies and inform the drug鈥檚 development.

Finding a new path

Asked what advice he鈥檇 give academics considering translational endeavours, Quezada says, 鈥淔irst, you need to want to do it.鈥� He鈥檚 frank about the fact that investing time on such efforts can affect researchers鈥� purely academic work, but he believes that a happy balance can be struck. 鈥淭he biggest challenge is to find the right partner that is going to help you get it to where you want to get it,鈥� he says. 鈥淎nd, second, you need to know where it is that you want to get to.鈥�

The CD25 project entailed a constant conversation about Quezada鈥檚 involvement, with both Tusk and Roche. The resolution of which has seen Quezada both publish influential papers on the molecule鈥檚 biology and make crucial contributions to the drug鈥檚 development.

鈥淭he most important thing is to get this drug to the clinic. We translational scientists need to understand that there are different goals and also different ways of measuring success,鈥� he says. He believes that聽

Today, Quezada continues to look out for ways in which his research might lead to new therapies. What鈥檚 vital for Quezada is that opportunities to save patients鈥� lives are not lost. Speaking of why he鈥檚 dedicated to increasing the profile of translational work, he cites examples of basic biology that he believes have major implications for further honing the effectiveness of immunotherapy 鈥� but which nobody has yet turned into therapeutic strategies. 鈥淭here is a large number of very good basic scientists,鈥� he says, 鈥渢hat just haven't seen it. It's not that they don't care. They just haven't realised that some of their findings, that they might think are very minuscule, could have a humongous impact.鈥�

Professor Sergio Quezada聽is group leader at The Immune Regulation and Tumour Immunotherapy聽group at the 果冻影院 Cancer Institute. He received a CRUK career development fellowship in 2010, and a CRUK senior cancer research fellowship in 2016

This article was originally published as a research feature聽by Cancer Research UK on 12th April, 2021.聽Author:

Further information聽

• Research paper:聽. Nature
• Immune Regulation and Tumour Immunotherapy聽- Prof Sergio Quezada
• 果冻影院 news:聽Promising pre-clinical results for modified antibody targeting CD25
• Interview: Developing a new immunotherapy to gain control of cancer
• Source: CRUK聽 - .
• Main image: 听(驰辞耻罢耻产别)
• AACR 2021 abstract: PL04-02 -