Chemical trick improves tumour treatment

‘I’ve been a rather diverse organic chemist but in my research there’s always a link with medicine and biology. I look at how life works at the molecular level, and what happens when diseases occur. Then I try to use my knowledge of chemistry to think of a way of tackling a disease,’ says Bauke Albada, associate professor at the One of Albada’s sources of inspiration is immune therapy for cancer, such as dosing patients with antibodies that inhibit the division of tumour cells. One way this immune therapy is used is in treating certain forms of breast cancer, alongside chemotherapy. The advantage of immune therapy is that it works in a more targeted way because antibodies seek out the tumour. A few years ago,
Albada developed a method for equipping antibodies with a chemical ‘hook’ to which you can quickly and precisely attach other things, including drugs that kill cancer cells. This gives the antibodies a dual function.

Dealing with reactions

For this ‘biogenic click chemistry’, Albada used an enzyme in order to change one of the amino acids (tyrosine) in the antibodies very precisely so that it starts chemical reactions with other specific substances. Albada: ‘The nice thing about this approach is that you can use antibodies that have already been approved as medical drugs. So with click chemistry you can easily attach all sorts of things to them, like toxins which make an antibody extra harmful for a cancer cell.
With click chemistry you can also link two different antibodies and study whether that produces new treatments.’ There are no applications yet, but the patent
on this chemical technology is now in the hands of Synaffix, a Dutch biotechnology
company that applies various kinds of click chemistry at the behest of pharmaceutical companies. ‘We have sold the intellectual property rights to the tyrosine click chemistry to Synaffix. The company was allowed to patent the technology as long as it supported our application for followup research. Synaffix has allocated 75,000 euros to the new project.’ At the end of 2023, Albada’s group received a grant of nearly one million euros from the Dutch Research Council (NWO) for joint research with Radboud University Medical Centre on using the same click chemistry in another way, namely to temporarily deactivate antibodies with a ‘mini-mask’. Albada: ‘The fact that a private company was investing in our research certainly helped us get this NWO grant.

Cut off the mask

The aim of the new project is to use click chemistry to equip antibodies with
molecules that literally get in the antibody’s way until an enzyme in the tumour cuts off the ‘mask’. Currently, if patients are given a dose of antibodies, less than 0.1 per cent of them end up where they are intended, says Albada. Along the way, the antibodies also attach themselves to places where they don’t belong, in organs and healthy tissue. ‘That causes unwanted side effects and makes the treatment less effective. Our idea is to make masks that prevent this, so that much more of the injected dose ends up at the right place in the tumour. If that works,
the antibody dose can be increased, while the side effects would be reduced. That
would be the ideal scenario, taking us a step further in the way we treat cancer.’

Fast clicks

Albada can build on research published earlier: in the literature there are quite a
lot of examples of masking antibodies. But earlier experiments were not very
successful and making the masks is very time-consuming. The unusual thing about Albada’s method is its combination of enzymes and chemistry. ‘With our click chemistry, we can attach many different masks – such as proteins or polyethylene glycol – more quickly to antibodies and then test whether enzymes can cut them off again. Then we’ll get an idea of which strategy works best.’ Two PhD researchers and one postdoc are going to work on this for five years.
‘We expect to get a long way in that time. I would be satisfied with a method that
works well for attaching precisely targeted masks to different antibodies. It would
be even nicer if we could demonstrate in a study in rats that this approach works.
Ideally, of course, this generates a series of nice scientific publications, and hopefully a patent too, with which we can get fundingfor further research.’