Dr Kate Griffiths on world-first shark-inspired drug

Dr Kate Griffiths on world-first shark-inspired drug

It’s a breakthrough garnering worldwide attention and avid investment: molecular scientists at AdAlta Limited, an Australian biotech company based at the La Trobe Institute for Molecular Science (LIMS), have achieved a remarkable feat of protein engineering that started with a sample of wobbegong shark blood and resulted in a humanised antibody that shows enormous promise to those suffering from certain fibrotic conditions – specifically, idiopathic pulmonary fibrosis (IPF).

Fibrosis refers to the formation of scar tissue. IPF, as the name implies, is a fibrotic condition of the lung tissue that has no precisely determined cause. It’s a progressive disease that kills 50% of sufferers within 3-5 years of diagnosis. The two currently available drugs for IPF can, at best, slow the progression of the disease. The prognosis is still grim, but the new discovery could be a game-changer.

A $10 million kick-start to clinical trials

Dr Kate Griffiths, an AdAlta senior scientist and research fellow within LIMS, has been a key driver of the research since its conception. She discussed her research and the reception that their candidate drug, AD-114, received with AdAlta’s initial public offering (IPO) on the ASX.

The IPO more than met their funding goal, resulting in a $10 million investment. For Dr Griffiths and her team, this marked a huge milestone.

‘It was really great. It was a real vote of confidence.’

Australian biotechnology research, according to Dr Griffiths, is not an overly favoured investment. ‘It’s difficult in Australia. I think the market’s slightly different in terms of willingness to invest and take risks in biotech – it’s a slow-return industry so I can kind of get it.’

The pre-clinical trials of AD-114 have been particularly promising, and the injection of funds means that Dr Griffiths and the AdAlta team can move forward with better planning, more collaboration and a certainty that scientists are rarely afforded.

‘What we’re going to be doing with this funding is further validating the lead drug. So we’ll be putting it into some more animal models to validate its efficacy. We’re looking at safe dosing ranges and toxicity – we’ve already done this in mice in quite high doses and had no observable side effects, which is great.’

The research team can then move into clinical trials in humans, usually in a small number of healthy volunteers in the first instance.

What we know about IPF

Dr Griffiths explains that there are several cell types that seem to be critical: ‘Fibroblasts, which reside in the lungs, and for some particular reason in fibrosis convert to myofibroblasts that start to produce excess collagen and other proteins… as well as fibrocytes which are thought to migrate from the bone marrow to the lung’. As the collagen builds in the lung tissues, they become increasingly less functional, but the exact triggers remain unknown. The usual cause of death in IPF is respiratory failure.

Shark blood, antibody genes and the i-body library

Dr Griffiths recounts the processes that ultimately gave the AdAlta team the recognition they now enjoy. ‘Working in the CRC for Diagnostics, we took a small amount of shark blood, [extracted] the RNA, and then made cDNA encoding the shark’s antibodies. So from that we made a library of antibodies that is several billion in size.’

The team examined the crystal structure of one of the shark antibodies and found that it had striking similarity to a human protein. So they took the gene for that human protein and built flexible loops onto it to create a new fully-human “i-body” library, with the loops doing the work of locking snugly into an antigen of interest, so (the i-body) is similar in size and structure to the shark antibody, but fully human.’

‘That was our real moment of “oh, I wonder what would happen…” It was really exciting to change the specificity of this human protein.’

‘There are two main libraries that AdAlta has worked on over the years: the shark antibody scaffold, and the fully human i-body scaffold’, says Dr Griffiths.

A therapeutic drug from the i-body library

Dr Griffiths and AdAlta scientists then selected a target antigen of therapeutic interest. In this case it was CXCR4, which is a receptor expressed on the outside of cells that helps them migrate strategically around the body, toward the lung and other tissue. ‘It’s also a potential biomarker, which is like a signature, of certain diseases like fibrosis and cancer.’

The i-body library is added to the CXCR4 on a stable surface, which is then washed to remove anything that doesn’t adhere. ‘You select out the really sticky, or the really good binders.

‘It’s like a sifting through of a whole large library of molecules to find the ones that bind with really good affinity.’

The team found a good CXCR4 i-body, which they gradually improved by tweaking certain parts of the binding loops and hence, AD-114 was born. They found it binds to CXCR4 with very high affinity, and, being human, ‘it’s more likely to be tolerated in the human body as a therapeutic.’

The extraordinary specificity and activity of AD-114

AD-114 halts the migration of the lung-bound fibrocytes, breaking the chain of IPF progression. It essentially uses the same binding lock-and-key system as immunoglobulins, an elegant method of stopping the action of that antigen.

But Dr Griffiths explains why it’s even better than an antibody: it comes down to the engineered loops of the i-body – which are quite long compared to traditional antibodies. ‘With its long loop the i-body has a tighter binding reaction.’

A world-leading expert on fibrosis, Dr Cory Hogaboam from the Cedars Sinai Institute, has tested AD-114 on fibrotic and healthy human lung tissue. Remarkably, it only blocked the migration of fibroblasts in patients with IPF, a level of specificity that we rarely see in medicine.

The joy of collaboration

AdAlta’s seminal research paper was recently published after years of dedicated research and plenty of collaboration, ‘which makes it really fun, and that’s where you get the great context of your work’.

The collaborative approach, to those who observe the fast-paced nature of modern science, seems commonplace now. We asked Dr Griffiths if scientists seem generally less focused on having ownership in favour of sharing knowledge to drive results. ‘It’s like we were talking about – the intersection of disciplines, where you get people with different specialties going, “oh yeah, I know about that, and you know about that – let’s try and put it together.

‘I think that’s the really nice thing about biotech actually. I really like that. You’ve got a common goal.’

Straddling two worlds and the future of AD-114

Dr Griffiths holds a dual research position, but she challenges the view that this might create additional pressures. ‘I think it’s great! We have access to great equipment and can share expertise and it’s so stimulating.

‘I feel very privileged, absolutely.’

AdAlta researchers are still investigating other applications for AD-114. ‘We’re testing it in an eye fibrosis model at the moment and we’re also testing in a liver fibrosis model. There’s also hypertrophic skin model. We haven’t started this, but we’re also planning to look at heart scarring and kidney scarring models as well.

‘The key to research is understanding and investigating the disease, combined with the drug development – that’s going to give the best outcome for patients.’

Dr Kate Griffiths is Research Fellow in the La Trobe Institute of Molecular sciences, La Trobe University, and a senior scientist with AdAlta. Read the team’s landmark publication here.

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