Crescendo Biologics pioneers a new approach to using antibodies in fight against cancer

CEO Peter Pack explains how unique Humabody drugs could have up to six targets at once and cause fewer side effects

For more than 40 years, the Cambridge region has led the way in antibody engineering.

From the Nobel Prize-winning discovery that began it all, to the creation of Humira, the blockbuster multi-billion pound antibody drug, Cambridge has pioneered the use of nature’s own self-defence system in the fight against disease.

So the region is the natural home for Crescendo Biologics, a company applying further innovation in the use of antibodies to create cancer drugs.

And it is doing so with the aid of mice that produce a key section, or ‘domain’, of an antibody that is fully human in nature.

Unlike those that we produce naturally, these domains can be strung together like building blocks and attack not just one target, but up to six at once.

It’s a potent weapon - a fact not lost on investors. Crescendo recently announced that it had secured $70million (£51million) in funding to take its lead drug candidate, aimed at certain forms of prostate cancer, into the clinic for trials.

Beyond that, its technology will be applied to fight other forms of cancer.

CEO Peter Pack told the Cambridge Independent: “I really like being here in Cambridge. It is the cradle of a lot of antibody companies - from Sir Gregory Winter starting Cambridge Antibody Technology (CAT). It leads within Europe, if not worldwide.

“It’s the best place to carry out antibody technologies. At least half of the company worked for CAT. It’s so important to be located here and benefit from the experience and the antibody engineering expertise.”

Antibodies, also known as immunoglobulins, are Y-shaped proteins that are deployed by the body’s immune system to fight invaders like pathogenic bacteria and viruses.

The base of the Y is known as the Fc (Fragment, crystallizable) region and helps ensure each antibody generates an appropriate immune response.

The arms include the sites that bind to such antigens, and are known as the Fab (Fragment, antigen-binding) region. Like a lock and key, the binding sites at the tip of the arms fit only a specific antigen.

The arms themselves feature a heavy chain and a light chainam of amino acids, each divided into domains known as constant and variable. Crescendo’s interest is in the variable, heavy domain, known as VH.

“Our platform is special because firstly it creates extremely small biologic proteins, based on the smallest possible immunoglobulin domains,” says Peter.

“Companies have shown that you don’t need the full Y-shaped antibody for specific binding to targets. You can bind with just the VH domain and have all the binding and specificity.”

Crescendo, based on Babraham Research Campus, produces these domains within what is known as a transgenic mouse: one that has had a foreign - in this case human - gene inserted into its genome. This enables it to produce human VH domains.

Some attempts to use antibodies produced by non-human species have relied on a process of ‘humanising’ them - modifying their protein sequences to increase their similarity to those produced by humans, making them more likely to be accepted by the body.

“Our platform is different because we enabled a transgenic mouse to produce fully human VHs. You don’t need to humanise it,” says Peter. “That’s really special.The mouse creates and optimises these VH domains, which are the smallest possible binding domain but based on human sequences. What the mouse produces is really the best possible starting point.

“The company has invested years and money into this mouse. It’s a kind of innovation engine, delivering the building blocks we need.

“We are taking these human VH domains and putting them together. We call this Humabodies because they are based on fully human VH domains.

“We can have anything between one and six building blocks, which we can nicely assemble into a kind of string of pearls molecules.

“A typical antibody usually binds one target. We can bind up to six targets and still retain a really small size.”

In this context, size really does matter.

“We have a much better biodistribution compared to conventional antibodies,” explain Peter “Our Humabodies – even if they are tri or tetra-specific, something you can’t do with conventional antibodies – go quickly through tissues and deeply into tumours. There is much better tumour retention.

“We can have a multi-specific construct that is still really small, getting deeply into the tumour, getting into cells, delivering drugs or have some kind of effect on mechanism.

“The small size, still being multifunctional, gives us a competitive edge over conventional antibodies.

“We get it in the tumour fast, we get more molecules into the tumour cells - we have a more potent molecule in the end.”

Antibodies have more than one tactic. By binding to an invader, they can disable the threat it poses by preventing it from attaching to cells and inhibiting its ability to spread.

Another process, called opsonization, prevents a pathogen from evading detection and serves them up as microbial food for immune cells known as phagocytes.

A further mechanism triggers ‘complement activation’ - in other words, by binding to the invader, the antibody calls in a cavalry of other proteins that can attach to the microbe or drill a hole in its membrane and kill it.

With up to six targets, Crescendo’s Humabodies can deploy a range of approaches.

“We have VHs that are not just binding,” said Peter. “They can activate something, or be antagonists, so they can dampen something down. This is ideal - especially in oncology.

“They have more than one function, which is the big advantage to conventional antibodies.”

Its lead drug candidate, CB307, is a T-cell engager, meaning it activates these immune cells so that they can destroy tumour cells by provoking clustering. Unlike some other attempts to do this though, it prevents this clustering away from the tumour, reducing side effects for patients.

“It’s really a new mechanism,” says Peter. “T-cell engagers are a unique approach to activate T-cells. What we achieved is to co-stimulate T-cells but our special mechanism is more specific and safer than normal. We’re activating certain types of T-cells only in the vicinity of tumour cells: that is new. And that is what investors and pharma companies have found highly interesting.

“We have developed a unique clustering mechanism, making use of our modular approach.” The drug candidate is bispecific - its two targets are a PMSA protein implicated in prostate cancer and CD137, a protein that helps the body fight tumour cells.

“It’s not activating just any T-cells. There is a safety feature that means we only activate tumour-specific T-cells and not something that would, for example, be auto-reactive, which would create inflammation problems,” explained Peter. “It’s the first one and we’ve now got the money to bring it into the clinic.”

By deploying just the VH domain, and not a full antibody, Crescendo ensure quick penetration of the drug and accumulation in the tumour - evidence that the full Y-shaped antibody is not always required.

“For some applications, a big antibody with the Fc part makes sense and is not a disadvantage. The constant domain can have some additional function,” said Peter.

“But sometimes it can be a negative, especially in the immuno-oncology field, which is the hottest field in oncology and maybe in the whole of life sciences.

“Now people have found that the Fc part can be counter-productive.”

Some drugs known as checkpoint inhibitors can end up being destroyed by macrophages within the immune system, alerted to their presence by the controlling Fc region.

As a result, some companies have begun to deactivate this part of the antibody.

“It’s like a burden. We’re avoiding it from the start. We have a bespoke biologic - built from modules and only the modules you need,” said Peter.

As its Humabody drugs edge closer to clinical use, Crescendo can be hopeful of writing its own chapter in the history of the Cambridge region’s extraordinary work in the field of antibody engineering.

Cambridge’s contribution to antibody engineering

It was in 1975 that Georges Köhler and César Milstein created the first monoclonal antibodies.

Working at the MRC Laboratory of Molecular Biology (LMB) in Cambridge, they succeeded in stimulating cells into making an unlimited production of antibodies, a feat for which they shared the 1984 Nobel Prize for Physiology or Medicine with Niels Jerne from the Basel Institute, Switzerland.

Initially developed from mice, early applications included identifying viruses, purifying drugs and testing for pregnancy, cancers, blood clots and heart disease.

In 1986, the first monoclonal - meaning ‘all of one type’ - antibody was fully licensed as a drug, used to help organ transplant patients.

But medical applications for mouse monoclonal antibodies are limited because the human immune system rapidly deactivates them.

Step forward Sir Gregory Winter, the master of Trinity College, Cambridge, and another LMB researcher.

He pioneered a technique to humanise mouse monoclonal antibodies by swapping out portions of it, making them less likely to provoke an immune response in patients. The technique was used to help develop Campath, a drug that is effective in the treatment of relapsing-remitting multiple sclerosis.

Sir Greg then developed methods to make fully human antibodies. Using a technique known as phage display, in which libraries of human antibodies are ‘displayed’ on bacterial viruses, the drug Humira was developed by MRC spin-out company Cambridge Antibody Technology.

Humira, the first fully human monoclonal antibody drug, was launched in 2003 as a treatment for rheumatoid arthritis.

Also used to treat psoriasis, it is now the world’s best-selling prescription medicine - and pulled in $16billion in 2016 alone.

Another LMB researcher, Michael Neuberger, developed a different method for making human antibodies. He used transgenic mice with human antibody genes, work that has helped to create several new human therapeutic antibodies.

By the end of 2017, 73 monoclonal antibody drugs had been approved - including 10 last year alone. They are used to treat breast cancer, leukaemia, asthma, arthritis, transplant rejection, immune diseases and cardiovascular diseases. They account for more than a third of new treatments.

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