How UK researchers commercialised CD25 as an immunotherapy drug target

But then, in 2010, the picture began to change. New data from cancer immunotherapy studies Quezada had been running in his newly established lab together with his colleague Karl Peggs, caused them to reconsider CD25. It looked like it hadn’t been the target that was wrong… it had been the antibody.

Fast forward to 2021 and Quezada is just about to address the meeting of the American Association of Cancer Research to describe promising early results of how an anti-CD25 antibody can indeed trigger an immune response that causes tumours to completely disappear in mouse models.

Quezada’s early work on CD25 was conducted in Jim Allison’s 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 – 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 – receptors that ordinarily function to keep any immune response proportionate to the need for them. And Allison’s demonstration that blocking these checkpoint receptors disinhibited T effectors, allowing them to destroy patients’ tumours, won him a share of a Nobel Prize.

Allison’s 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. “That’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,” he says. “I said, ‘This is exactly what I want to be doing. I want to be working at this interface’.”

At this point, Karl Peggs, a clinical fellow with whom Quezada had worked with in Jim Allison’s New York lab, was instrumental in recruiting him to UCL. Peggs had already moved to London and he told Quezada that if he moved to UCL, he could plug a gap between clinical trials and basic immunology research.

A grant from CRUK was instrumental in securing the position. “We first supported Sergio through a CRUK career development fellowship back in 2010,” says Matt Kaiser, Head of Careers and Discovery Research at CRUK. “This allowed him to bring his expertise to the UK and establish his own research group.”

Yet, despite his and CRUK’s translational ambitions, Quezada didn’t arrive at UCL with a specific drug in mind. “I don’t think that’s how it works,” he says. “These things are organic. It’s like a little plant, they emerge.”

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’s group – controversially ­­– found evidence that these drugs could also deplete Tregs in tumours and that this was a vital part of their action.

This reignited interest in CD25 because – unlike checkpoint receptors – 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 – they found their newly designed antibody caused a stronger immune response against the cells it bound to – which in turn caused tumours to shrink. “That was kind of the eureka!” 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’s mind in New York, had taken root in London.

Regular discussions of translational opportunities were a key part of Quezada’s CRUK fellowship, and soon after he’d 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 UCL redoubled their efforts and found a way to file IP and establish a collaboration with Tusk.

Asked what advice he’d give academics considering translational endeavours, Quezada says, “First, you need to want to do it.” He’s frank about the fact that investing time on such efforts can affect researchers’ purely academic work, but he believes that a happy balance can be struck. “The biggest challenge is to find the right partner that is going to help you get it to where you want to get it,” he says. “And, second, you need to know where it is that you want to get to.”

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

“The 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,” he says. He believes that academic institutes and funders are increasingly valuing accomplishments in drug development and real-world impact.