Newly elected both as a Fellow of the Academy of Medical Sciences and Fellow of the Royal Society, John McCafferty has spent more than 3 decades transforming antibodies from natural defenders into medicines that have improved millions of lives.

A gradual graduation

 "I was born and brought up in the Gorbals area of Glasgow and, like many of my generation and background, I was the first in my family to go to university," says John.

Drawn by a fascination with how living systems work, John studied biochemistry and pharmacology at the University of Strathclyde before undertaking a PhD through the University of Glasgow and the Beatson Institute for Cancer Research.

What began as curiosity about biology evolved into a deeper interest in the molecular mechanisms that underpin life itself, which then brought him to Cambridge, one of the most influential scientific environments in the world.

In 1990, John became one of the founding scientists of Cambridge Antibody Technology (CAT), a young company built around a bold idea: that antibodies could be engineered rather than simply discovered.

His time at the MRC Laboratory of Molecular Biology (MRC-LMB), working in Greg Winter’s lab, raised his sights to a higher level.

"This was the home of multiple Nobel Prize winners, some of whom were still there sharing the canteen with us ‘mere mortals’," John says. " There was a real buzz in Greg Winter's lab at the time and a sense that anything was possible. For me, it ‘raised the bar’ scientifically."

A moment of high excitement

 The polymerase chain reaction (PCR), published in 1985 by Kary Mullis, had revolutionised scientists' ability to amplify genes.

Shortly after, researchers had demonstrated that antibody genes could be copied and manipulated using these new molecular tools. The challenge was how to search vast collections of antibody genes and identify those that encode rare molecules capable of binding a specific target.

Existing methods were cumbersome. One approach involved using lambda phage, a type of virus that infects and lyses bacterial cells to express antibody libraries. These were grown on bacterial plates before transferring the resultant antibodies onto filters and screening them with radioactive probes.

"It was slow, tedious and limited in scale and flexibility.”

"We had the idea of expressing the antibody on the surface of filamentous phage, thereby creating a ‘package’ coupling the antibody gene and the encoded antibody within a phage particle," says John. "That would allow direct ‘panning’ of the phage particle based on binding activity."

The implications were profound. Researchers could create libraries containing billions of different antibody variants suspended in solution and rapidly select antibodies simply by identifying the particles that bound to a target.

I knew we were onto something after the first ELISA experiment with phage particles on a 96-well plate. You can watch in real time as the colour develops in the intended wells and not in the controls. A moment of high excitement!

Within 12 months of starting, the work became the landmark 1990 publication in Nature that first demonstrated antibody display on filamentous phage, a breakthrough that would become known as phage display technology.

A year later, John and colleagues from CAT and MRC-LMB showed that human antibodies could be selected directly from non-immunised antibody libraries, removing the need for traditional animal immunisation and opening the door to a new generation of therapeutic antibodies.

Together, the advances transformed the field.

The underlying concept of linking a protein's function to the gene that encodes it has inspired a family of technologies including ribosome display, yeast display and mammalian display, allowing the development of various alternative non-antibody scaffolds.

Today, phage display has become a standard tool throughout the biotechnology and pharmaceutical industries around the world. The importance of the breakthrough was recognised in 2018 when the Nobel Prize in Chemistry was awarded to Sir Gregory Winter.

The technology is now being exploited by scores of biotechnology companies and most of the world’s big pharmaceutical companies including Astra Zeneca, GSK, Roche, Genentech, Merck and Sanofi.

It has led to at least 15 approved antibodies with many more in development. That is both exciting and very satisfying.

One of the most significant examples was Humira (adalimumab), a treatment for inflammatory diseases including rheumatoid arthritis, Crohn's disease and psoriasis. Developed using phage technology by colleagues at CAT, the drug went on to become the world's best-selling medicine for many years and remains the highest-selling pharmaceutical product in history on a cumulative basis.

An industry around antibodies

Before being acquired by AstraZeneca in 2006 for £700 million, CAT became one of the earliest success stories of the UK's biotechnology sector, growing to around 300 employees.

For John, however, the success of CAT was never the end of the story.

In 2012, he founded IONTAS, a biotechnology company using phage display to develop novel antibody therapeutics. Working with partners across the pharmaceutical industry, the company generated multiple drug candidates that progressed into clinical development before being acquired in 2020.

At IONTAS, John invented KnotBody® technology, a novel platform that combines antibodies with naturally occurring venom-derived peptides to tackle ion channels, proteins that regulate electrical signalling throughout the body and play important roles in autoimmune diseases, chronic pain and neurological disorders. Despite their therapeutic potential, ion channels had long proved difficult targets for antibody medicines.

To realise the technology's potential, John founded Maxion Therapeutics, where he now serves as Chief Technology Officer. The company has raised more than £70 million and is advancing highly selective ion-channel-targeting therapies from bench to bedside.

"Among different target classes for drugs, ion channels have been a ‘blind spot’ for antibodies," he says. "I'm excited by the work we're doing at Maxion Therapeutics, where we've developed ways of generating and characterising antibody drug leads to this difficult target class and are en route to the clinic."

“I have founded 3 companies and my principal driver every time was a love of science,” John says. “I followed a path to pursue that love of science, and this pathway involving hopping between academic and commercial science.”

Currently, John also leads a group within CITIID at the Department of Medicine, University of Cambridge, where he applies advances in recombinant antibody technology to global health challenges including snakebite envenoming.

Building on his previous work, John’s group is working on replacing century-old animal-derived antivenoms with defined, characterised antibody cocktails that are safer, more effective and easier to manufacture.

Asked what advice he would give to budding entrepreneurs, John returns to the importance of passion.

Find something that you can get passionate about. It is easy to say and hard to do, but if you can do that it makes the rest of the journey so much easier. That passion, together with some resilience, makes it much easier to navigate and overcome the inevitable bumps in the road. You also need to be willing to take a risk sometimes.