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Greg Winter: Pioneering antibody drugs

Today the MRC is honouring two of our most eminent scientists with the MRC Millennium Medal which recognises research that has led to significant health and economic benefits. In the second of our profiles of the winners, Katherine Nightingale talks to Sir Greg Winter, who pioneered techniques that have led to antibody therapies for cancer, and diseases such as rheumatoid arthritis and multiple sclerosis. He has established hugely successful spin out companies and continues to develop new types of drugs.

Greg Winter (Copyright: Tony Pope)

Greg Winter (Copyright: Tony Pope**)

It was an elderly woman with lymphoma who changed things for Greg Winter. It was 1989 and the patient at Addenbrooke’s Hospital in Cambridge was the first person to take Campath-1H, a human antibody that had been fused with parts of a rat antibody to attack cancerous lymphocytes.

Greg was behind the technology that had ‘humanised’ the antibody. At the time, the therapeutic promise of antibodies derived from rodents was hampered because patients’ immune systems would attack the foreign antibodies. Though Greg didn’t know it then, his humanising technology would go on to create one of the most successful classes of drugs ever.

“I remember going to see this sweet lady who was sitting doing her knitting and talking about how she just wanted to hang on a little longer for her husband. She had been at death’s door and had started to recover,” says Greg.

“I remember thinking “we’ve done this”. It was a turning point, I’d only really been interested in laboratory research and I realised I had to do something with this technology — I couldn’t just walk off back to the lab.”

An academic entrepreneur

Greg’s technologies are involved in around 65 per cent of marketed antibody drugs today, including Humira and Herceptin, and antibody therapies had a global market valued at £25 billion in 2010. But while his science has gone on to be applied on an extraordinary scale, Greg sees himself foremost as an academic.

His research career, both before and after he worked on antibodies at the MRC Laboratory of Molecular Biology (LMB) has been characterised by asking fundamental scientific questions.

Greg had a background in protein structure research, and had been working on the engineering of enzymes and was now interested in building new proteins. But César Milstein, who along with Georges Köhler had discovered a way to make rodent antibodies to attack cells and proteins involved in disease, had become Head of the LMB’s Division of Protein and Nucleic Acid Chemistry and was keen for Greg to switch focus to antibodies.

Greg wondered if he could engineer entirely new proteins using an antibody ‘scaffold’. He saw that all antibodies have the same basic structure — a common scaffold onto which are attached different protein ‘loops’ that make them attack a specific structure. He wondered whether he could transplant loops from one antibody to another, and thereby transfer this specificity.

Greg decided to take the loops from a mouse antibody with a known target and transplant them into a different antibody of known 3D structure, in this case a human antibody. At that point, the experiment was more to prove the principle than for medical benefit.

“But then I realised that it would also be very practical if it worked because it would be a way of producing an almost human antibody,” says Greg.

The first success

After 18 months of work, Greg and his colleagues had succeeded in swapping the loops. Accused of a fluke, and with thoughts turning to medical applications, Greg knew he needed to try his technique in a rodent antibody that already had therapeutic potential.

He began working with Herman Waldmann, a clinician scientist at Addenbrooke’s Hospital whose rat antibody Campath-1 had been showing promise in patients*. Greg and his colleagues humanised the antibody, and Campath-1H was born.

Tests of Campath-1H in patients, including the woman who changed Greg’s outlook, were successful. That same year, 1989, the technique was licensed to a range of companies who realised it could resurrect the therapeutic mouse antibodies that had been languishing in their labs.

However, at that stage, Greg wasn’t sure whether simply humanising rodent antibodies would be good enough, so he started exploring ways of making human antibodies from scratch to eliminate the danger of an immune response. This involved creating and screening large and diverse libraries of human antibodies to find ones that would attack the disease of interest.

Faced with competition from the US and with no way of increasing the size of his research group at the LMB, Greg realised he needed to set up a company of his own to explore making fully-human antibodies.

Spinning out

Cambridge Antibody Technology (CAT) was set up in 1989 and soon established a technique for creating human antibodies in bacteria. He’d dabbled in consultancy but Greg knew little about business. “It was stressful and time consuming, and not many people really believed in antibody therapeutics — we almost ran out of money in the early 1990s. But by the mid-1990s antibody drugs were appearing on the market and things picked up.”

Greg stepped back from CAT in the mid-1990s to “go back to a quiet life in the lab”, but all the while continuing to work on questions that had potential practical application as well as being interesting theoretically.

His desire for a quiet life didn’t stop him from co-founding Domantis in 2000, another company aiming to make drugs based on the smallest functional unit of antibodies. And in 2009, he established Bicycle Therapeutics, another spin out aiming to develop a new class of drug that behave as mini-antibodies.

CAT was sold in 2006 to AstraZeneca for £700 million and Domantis went to GlaxoSmithKline in 2006 for £230m. The MRC has received around £390m in income from Greg’s intellectual property.

A fundamental question

For Greg, lab-based discovery science is key to finding solutions to medical problems — even if the researchers don’t know it at the time.

“Sometimes it’s better to do basic research and be opportunist. I stumbled across humanising antibodies — I was interested in something else and then realised there was a more practical dimension to it. That’s often the beauty of fundamental research.”

He believes strongly in the importance of fundamental research. “Nobody else is going to fund discovery science if the Government doesn’t do it. No one else is going to give you money to do work that might yield benefit in 20-70 years. We need to maintain a scientific cadre of people in the UK funded by the Government to work on both basic and more applied research,” he concludes.

 

* Text edited 18/03/2013 at the request of Professor Waldmann.

**The image used in this article has not been released under our Creative Commons Attribution 3.0 Unported Licence.

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