How F-star is supercharging the immune system in fight against cancer
An exclusive interview with CEO John Haurum about F-star's extraordinary work on Babraham Research Campus
In June 2017, F-star struck a deal with pharmaceutical giant Merck in Germany that could eventually be worth more than one billion euros.
It was another sign that this relatively small biopharmaceutical firm has some extraordinary technology on its hands.
F-star is engineering special antibodies – the molecules in our immune system that help to fight infection – to use as potent drugs in the fight against cancer.
To understand the uniqueness of F-star’s work, however, we first need a quick lesson in immunotherapy.
CEO John Haurum explains: “You can take antibodies and engineer them in a laboratory setting and make them specific for cancer targets on the surface of tumours.
“This technology has developed significantly over the last 20 years in several indications such as breast cancer. These antibodies are very specific and can be used to kill tumour cells in patients or inhibit their growth.
“More recently it has been found that you can also generate antibodies against components of the immune response itself – the white blood cells – and use those to enhance the immune response that is ongoing in cancer patients.”
This might sound counter-intuitive, given that white blood cells drive our immune response. But it’s a complex system, with ‘regulatory’ cells suppressing the function of ‘effector’ cells to prevent the body attacking itself under normal conditions.
In cancer, the immune system can become confused – with tumours co-opting the regulatory cells to stop the effector cells doing their job. The body’s own checks and balances fail.
“With our therapy, we hope to modulate those checks and balances in the immune system and accelerate the immune response against tumour cells,” explains John.
Immuno-oncology – using the immune system to fight cancer – has proven very promising in certain cases.
Twenty per cent of patients with advanced skin cancer, for example, who were destined to die within a year, were effectively cured and went on to live for years, tumour free, following therapy developed elsewhere that targets CTLA-4, one of the ‘immune checkpoints’ that regulate our immune response.
“All companies in this space are trying to find improved therapies that will have stronger potency and expand the number of patients who will respond,” says John.
This brings us to F-star’s approach and its use of ‘bispecific antibodies’ – molecules that are capable of two activities.
“Antibodies are Y-shaped structures,” explains John. “On both ends of the Y, they have a binding ‘specificity’.”
Like a key that only fits a certain lock, this specificity ensures the antibody attaches only to the correct target, or antigen.
“Bispecific antibodies have typically been made by having two half antibodies symmetrically come together from either side,” says John. “You have specificity one and specificity two on either side of the Y. Basically, it’s a two-in-one drug.
“F-star’s version is slightly different. We leave the top part of the antibody intact, with one specificity at the top, with two binding sites.
“We introduce the second binding specificity at the bottom of the molecule – the stem of the Y. We essentially have a new antigen-binding site there, making it bispecific or dual action, binding two different antigens. This brings a wealth of advantages regarding the manufacturability of the molecules as well as the modularity in pairing one target with another.
“In the immuno-oncology space, the aim through this bispecific activity is to have more effective agents to break beyond the limited number of patients who respond.”
The Babraham Research Campus company is screening many potential targets and looks for novel responses that wouldn’t work using a single agent or, as other companies are exploring, a straight combination of antibodies.
“We’ve got several approaches,” explains John. “Typically, we’re targeting proteins or glycoproteins on the surface of the cells. It could be a surface structure on a tumour cell and another on an immune cell.
“You could have the antibody drug redirected or targeted preferentially towards the tumour tissue if one of the specificities is a tumour cell antigen.”
In other words, creating a key at one end of the antibody that fits only into the lock of a cancer cell sends the drug into the heart of the tumour, where it can unleash its weaponry. And, of course, F-star’s bispecific antibodies have a double payload.
“You could also have the T-cells or white blood cells being pulled into the tumour cells through the redirection mechanism, which is a key goal. That’s something you would not achieve with an antibody combination approach – only with the bispecific antibodies. You are aiding the immune response by localising the tumour,” explains John.
The bottom of the Y-shaped antibody is known as the constant or Fc region.
Once an antibody has bound to its target, this region presents itself for attachment to ‘macrophages’ – the large white blood cells that engulf and destroy invaders such as cancer cells.
“That happens slightly higher up in the molecule, so the change we make to the very tip of the constant region doesn’t impact this – the activation of the immune system by the Fc region is still ongoing,” explains John.
F-star’s antibodies typically do their work by modulating the function of the structures to which they bind.
“For example, if it’s a growth factor or a stimulatory receptor that somehow drives the tumour growth, then having an antibody to block it could be a function,” says John.
It’s this approach that F-star takes in its most advanced product, a drug known as FS118, which features in its deal with Merck.
This bispecific antibody binds to two molecules.
One is called PD-L1 and its usual role is keeping the immune system in check, binding to immune cells to prevent them from being over-active. In the cancer setting, however, it prevents the immune system from attacking tumour cells. F-star’s drug corrects this by attaching to PD-L1, preventing this immune suppression.
The second molecule targeted, LAG-3, is another that inhibits immune activity.
Early studies are very encouraging and a clinical trial is due to start in the first half of 2018.
“It’s a programme that will potentially be applicable across a number of different tumour types. It is destined to work in patients where these regulatory mechanisms play a role,” says John.
F-star has a strong pipeline of other drugs, many of which could work broadly across different cancer types.
It is also working with American firm Denali Therapeutics, which has expertise in neuro-degenerative diseases, to create antibodies for the delivery of medicines across the blood-brain barrier into the central nervous system.
John, who completed a PhD in immunology in Oxford, expects F-star’s diverse, 85-strong team to grow, perhaps to 100, in the coming year – and there’s no denying his own passion for the work.
“I think it’s completely fascinating,” he says. “A lot about the immune response is still unknown. That’s a source of curiosity, excitement and optimism for me. There are going to be additional discoveries that are going to benefit patients.
“At the time of my PhD I had no idea how we could apply this molecular understanding of the immune system to help patients. It’s been quite remarkable what’s happened.”
He is excited about how personalised medicine, along with gene therapy and cell therapy, is poised to transform medical care.
“It’s a really important evolution in terms of how society handles the burden of disease,” he says.
“If you go back 10 years, there were products approved for breast cancer but only a small proportion of patients really benefitted. That is inefficient from a societal point of view and burdensome for the patient in terms of side effects.
“Where we are going is that the selection of a patient to go on a specific drug will depend on a molecular understanding of that patient’s cancer or other disease – a personalised approach.
“This will mean that the treatment should be more effective both from a financial point of view and, more importantly, from the point of view of the patient.”
F-star, you sense, will play a critical role in that.
F-star is rising
F-star’s business model seems almost as ingenious as its ‘Modular Antibody Technology’ platform.
Rather than sell off the whole company when a big pharmaceutical company wants to commercialise one or two of its drugs, F-star wraps them up in a new entity that can be sold without impacting the rest of the company’s pipeline.
Its headline-making deal with Merck, worth an initial 115 million euros, is a prime example.
“The agreement is structured as an option to buy,” says John. “We established a new separate entity – F-star Delta – and the five programmes that are the subject of the agreement are licensed into F-star Delta. Merck has a right to buy F-star Delta but the rest of the company is not impacted by this right – it’s independently owned by our shareholders.
“For this right, Merck paid an aggregate upfront of 115 million euros and as part of that there is an option fee to the shareholders, a licence payment into F-star and R&D funding included. There are also milestones payable included very early in the project period depending on progress. That makes up the 115 million euros.
“A work package has been agreed for the five programmes. We are still responsible for progressing them and we will take FS118 into the clinic and continue the development of the four other programmes.
“The work package has a timeline of a couple of years. When we have delivered that, it triggers the option.”
The total fee payable could exceed one billion euros if everything proceeds well.
“If they choose to acquire F-star Delta they would pay a good portion of that and then there would be subsequent milestones further down the line,” adds John.
“For me, the beauty of this model is that it parcels up the value in discrete packages and you are able to agree a value between the parties without having to accept a discount on the remainder. Other companies selling themselves in mergers and acquisitions often suffer from a sour-sweet feeling that they got a lot of money for their most advanced programme but didn’t really get anything for the rest.”
So far, F-star has developed four entities – F-star Alpha, F-star Beta, F-star Gamma and F-star Delta – and raised more than 200 million euros in non-dilutive funding.
“If we have programmes that are successful, the number will be higher,” says John.