Allan Bradley, Kymab founder and CSO, talks about his ambition to find better treatments for some of the world's most pervasive diseases.
When, as a young PhD student in the 1980s, Allan Bradley worked with Nobel Prize winner Martin Evans on developing and modifying the first embryonic stem cells, he could not have imagined that his work might one day help to develop new treatments for cancer or to discover new pathways to vaccines that could push back the diseases that wrack the world's poorest.
Today, Kymab, the company Allan founded, has partnerships with leading researchers that will deliver the medicines across cancer treatment, disease of the blood and infection. Supported by investment from Bill and Melinda Gates Foundation, Wellcome Trust, Malin plc and Woodford Investments, the growing company based near Cambridge UK has, in its grasp, the means to accelerate development of new treatments.
But where did the vision for Kymab come from? What was Allan’s path from student to company founder?
The usual route
In outline, Allan's career is not unusual; a university education and PhD in the UK, a stint in the US and then return to the UK to set up a lab.
But his career differs in detail. His PhD was with Martin Evans, who shared a Nobel Prize for the work to develop mouse stem cell technology that Allan and the Evans' lab worked on. His stint in the US was at Baylor College of Medicine, one of the top institutions in the US and a partner in the Human Genome Project. While at Baylor, Allan created two biotech start-ups.
And when he came back to the UK, it was as Director of the Wellcome Trust Sanger Institute — Europe's foremost genomic institution, which made the largest single contribution to the finished human genome.
Each of these experiences shaped his view of how lab research might make a difference to health. And that's when he becomes passionate about Kymab.
"For a biotech company to try to affect the lives of millions of people is really profound. I've had people say that one of the most important things I have done is to found this company, because of that potential impact. It is potential now, but I think it will be realised."
Kymab is one of many antibody companies and but one of a swarm of medium-sized companies in a competitive ecosystem, each vying to bring new treatments from the discoveries and vision of their founders.
Allan argues that, because Kymab's technologies produce human antibodies, it is among the fittest. The Kymouse™ that underpins the company contains a full set of immunoglobulin light and heavy chain genes that can produce 10 trillion different antibodies. The value of fully human antibodies suffuses all the company's projects.
"Immune systems of human, mouse, rat and rabbit have diverged over evolution," he says, "with the result that antibodies found in non-human species might not be effective or that the antigens we need to target are invisible to the non-human system. Kymab's antibodies mean we can accelerate development and be more confident of valid results in human patients."
Antibodies are in the vanguard of Kymab's search for new cancer treatments: the company's other foci are aberrant immune response in transplantation, blood diseases, and infection.
At its very founding in 2010, the young Kymab identified infectious disease as a focus.
"In more prosperous countries, antibiotic resistance is rightly recognised as one of our greatest clinical challenges," says Allan, "while in lower-income countries, there are devastating diseases for which an effective treatment is lacking.
"Human antibodies can serve as novel therapeutics and improve the discovery and validation of effective vaccines."
Allan emphasises that the impetus and direction owes a great deal to the work and support of Dr Glenn Friedrich, now Kymab's COO. Together they assembled the scientific and business plan, identified funders, recruited the early team, dreamed up a name and identified laboratories.
"We had initial discussions on areas of unmet need to which the new company might make a unique contribution, but could not act on these until the first version of the mouse was ready."
The first few of years of Kymab's existence were, therefore focused on developing the Kymouse™ platform, culminating in publication of the technology in Nature Biotechnology in 2014. With intellectual property in several key areas, Kymab also licensed its technology to Novo Nordisk in 2013, providing further validation of Kymab's achievements in its first three years.
"As the performance of the platform became apparent, we turned our attention to the discovery of new therapeutics in human disease,” says Allan.
The Kymab model today is to build a product pipeline independently and through product partnerships: "We want to co-develop new clinical products with leading partners," says Allan, "leveraging our intellectual knowledge and our platform in areas that we share with a partner."
The company's most recent partner is MD Anderson Cancer Centre; other partnerships include the Gates Foundation and Wellcome Trust Sanger Institute.
"Our partnership with MD Anderson is predicated on our skill at making effective antibodies against difficult targets. It's something that Kymab can uniquely do, with our core science and technologies."
Allan emphasises that part of Kymab's offer is that its technology means it is flexible and fleet of foot. He accepts that this could be a weakness as well as a strength, if its flexibility diverts it from its key projects.
"In our leadership committees, we have battered the issues of where we can most effectively place our efforts," explains Allan. "We have a clear focus in our four therapeutic areas and these will bring success.
"We're not a box of clever technological tricks, but a substantial, strategised company and have recruited bright leaders in each therapeutic area."
Building a Better Mouse
Kymab today seems a long way from Allan's early days in mouse embryology, but there is a clear trajectory from modifying single genes to engineering mouse chromosomes to tackle human disease.
In 1978, when Allan went to the University of Cambridge, he was initially focused on physical sciences, but this period ushered in a pivotal era in genetic modification, which caught his imagination. Only three years separate his first PhD work with Evans on incorporating cells into mouse embryos and, in 1984, their first model of human disease made by inactivating a mouse gene.
'It was an incredible time - great co-workers such as Liz Robertson and great competition from labs around the world," says Allan. "You need both of those - fantastic people in your partnerships and the spur of competition to drive you on."
From the earliest days, his research blends biology and technology - studying developmentally important genes, immune system genes, disease genes and cancer genes alongside methods to target genes for disruption or to extract tiny amounts of DNA for analysis.
In each of his appointments, Allan and his teams have led the development and adoption of technologies that made mouse chromosome engineering possible - and to give birth to Kymouse™.
Science, Sponsors, Society
Kymouse™ was recognised by the Bill & Melinda Gates Foundation and the Wellcome Trust as an important tool in the search for effective vaccines when they committed more than $6M to Kymab by way of research funding in addition to their $70M equity investment.
How do vaccines fit into a biotech startup?
Until Ebola and other emerging infections, vaccine research was the handmaiden to pharmaceutical science, in part because of feeling that the returns aren’t there in simple, prophylactic medicine or in markets that tend to be the poor and disadvantaged. And it remains an incredibly difficult area of research and development.
"Kymab is engaged in contemporary vaccinology because vaccinology is quite antiquated," says Allan, simply. "We are bringing modern molecular tools to the discovery of good antigens. And, remarkably, we are one of the biggest using the human immune system to drive vaccine development."
Kymab's pipeline includes vaccine targets in HIV, malaria and typhoid fever. These programmes are supported by the Gates Foundation Partnership, which recognises that the power of the Kymouse™ system could discover better vaccine targets and lead to validated, fully human vaccine products.
"For a biotech company to improve the lives of millions of people is really profound," Allan says, warming to the theme. "In a very real way, the biggest impact we can have will be in infectious disease, if we measure the number of lives that could be saved or improved."
But passion does not inevitably lead to profit or success. Allan points to the company's vaccine work as an example of synergism in Kymab, arguing that it isn't a big ask for Kymab to achieve a leading position in vaccine development for both higher-income and lower-income countries.
"Some vaccines such as adult flu vaccines, have made big returns for pharmaceutical companies. And, of course, we can realise income from our products in higher-income countries where, a malaria or typhoid vaccine, for example, would be welcomed by travellers. Higher-income countries are 20% of volume but 82% of sales of vaccines globally."
Allan knows that Kymab must be known for a success in therapeutic intervention and argues "We're about using our technology where we can make a difference and the therapeutic and the vaccine routes are mutually supportive, validating each other and not distraction from a core purpose.
"It is a difficult path, but one I believe we can and should follow. Let's be clear - when we're at a JP Morgan Conference, we want to be known as a leading therapeutic antibody company, with specialisms in blood, cancer or metabolic disease. If we can't achieve that, we have failed."
Nevertheless, he emphasises how healthy the relationship with the Bill & Melinda Gates Foundation is for Kymab, because millions of people could benefit from the partnership.
Can vaccines make commercial sense? Yes, argues Allan, but that is not the only point.
"Our business drive must be to build the programmes that will appeal to investors and bring return to those who invested their money and their partnerships with Kymab. At the same time, the idea that Kymab - a relatively small company - can have a huge societal impact really excites me.
"We have the opportunity to make a real difference to the lives of many people, because of the precision and quality of our technologies and the support of our backers and partners. It’s about better medicines."
Bench to Biotech
Allan's passion is complemented by his remarkable entrepreneurial track record.
He co-founded two companies while at Baylor; Spectral Genomics, acquired by PerkinElmer in May 2006, and Lexicon Genetics Incorporated, now Lexicon Pharmaceuticals. Those experiences influenced his vision for translation of the Sanger Institute's hugely respected research.
"When I arrived at the Sanger Institute in 2000, the previous Director John Sulston had built an organisation of 600 staff who had delivered the UK's share of the Human Genome Project draft - and over the next three years we completed almost one third of the freely accessible human genome. John had also developed pathogen genomics programmes, all world leading. What a legacy.
"My aim was to add biology to that genomics powerhouse - to ensure all those amazing discoveries could find a place in medical research and development."
Allan - who describes himself as an educator - recruited a new cadre of researchers to form the Sanger Institute’s new Faculty. Many were biologists, working with animal models, but he also strengthened the Institute's Human Genetics programme.
At the same time, other genomics projects were closed.
"It was a harrowing time for those affected and very difficult for me to institute the developments. The Sanger Institute had never made such large changes. But I know we had to find a new scientific niche where our science could flourish, founded in new skills and unique attributes in large-scale, genomewide genomics driving biology."
Allan also led the transition to a more commercially aware Institute, working towards a Translation Office to ensure that the potential of Institute research was realised. Today the Sanger Institute has formal partnerships with GSK, AstraZeneca and others and has given birth to four spinout companies. Kymab was the first.
Beyond a Biotech
Allan faced two familiar challenges in making Kymab pharmaceutical contender. The first was funding for the company - a given - and the second was the technical development to make the Kymouse™.
His team were engineering mouse chromosomes on a scale beyond that of any other group, inactivating the mouse immunoglobulin system and replacing it by a functioning human system. In developing Kymouse™, they inserted 5,400,000 base-pairs of stable, functioning human DNA into the mouse genome. But this remarkable success was merely a foundation.
"Our Nature Biotechnology paper [describing Kymouse™ in 2014] was a great boost, but we have had to work hard to build the lean and efficient platforms around it. That is where we are now: we have well-designed systems and a wonderfully motivated and talented group of people working on projects throughout Kymab."
It might be thought that Allan's close association with the Wellcome Trust would ease his search for financial backing, but he says the negotiations were difficult.
"The Trust Investment Division rightly want to ensure that the charity’s money is wisely invested - and they are very good at their job. It was not an easy ride," he recalls.
With initial financing secured and Kymab beginning to grow and demand more time, Allan stepped down as Director of the Sanger Institute, handing the reins to cancer geneticist Professor Mike Stratton. Allan retains a very productive lab at the Institute - as one of the most-cited scientists in Europe, he's had more than 3000 citations of his research every year since 2006 - alongside his role as Chief Scientific Officer at Kymab.
Given his track record, it's not surprising that Allan's ambition for Kymab is, well, ambitious.
"I believe that Kymab has the science, the technology, the expertise and the knowledge to become the Inspirational home of modern molecular biology developing drug substances, a major player in the sector. We have to aspire to be a success that delivers to our investors, our partners and to patients."
The Royal Society citation for Allan's 2002 election as Fellow reads in part: "It is impossible to open an issue of a major journal nowadays without coming across an article that describes the consequences of mutating an endogenous gene in mice. The generation of these mice is based on concepts and techniques that can be traced back to experiments performed and published by Bradley fifteen years ago."
Today a company, an approach and an industry sector are all based on these achievements.
The legacy seems less important to Allan: his passion with compassion returns when he talks about the financial success that is necessary to achieve his healthcare ambitions.
"If financing and healthcare impact are aligned, then we can make significant contributions to improving disease outcomes in our target areas that include cancer, heart disease and haematological disease, but also infectious disease in lower-income countries."
"I'm very taken by the simplicity of the first line of the Wellcome Trust's Philosophy: 'Good health makes life better'. At Kymab, we do difficult things to make that simple assertion a reality."
Read about the Gates Foundation Partnership