By: Jamie Morton
New Kiwi-led research could help realise the powerful promise of a new type of cancer treatment.
The million-dollar project centres on what are called antibody-drug conjugates, or ADCs.
While the concept of how they fight cancer has been around for decades, it’s only been in recent years that ADCs have delivered some clinical successes.
It’s long been known that certain antibodies can recognise markers on the surface of tumour cells, allowing them to target a patient’s tumour.
In an ADC, a drug that’s able to kill tumour cells chemically binds to the antibody before it’s taken up into the cell and the drug is released, thus directing the toxic effects selectively to the tumour.
The approach has proved effective in some cases, but in others has made little impact.
“Mostly, that’s because it’s a very complicated system,” explained the University of Auckland’s Dr Moana Tercel, also a senior research fellow at the Auckland Cancer Society Research Centre.
“You need an antibody that is selective for tumour cells, a very active drug, because the antibody can only carry limited amounts, and a way of linking them together that is stable while the ADC circulates around the body, but is cleaved when it’s inside the tumour cells.”
Over recent times researchers have made headway in getting around all three hurdles.
Three ADCs – designed for metastatic breast cancer, a type of leukaemia and some lymphomas – have been approved in the last six years, as new anti-tumour agents and more than 60 different ADCs are currently being tested in patients around the world.
Tercel said while the potential was great – new versions were being designed to target a range of blood cancers, melanoma, and prostate, lung, breast and ovarian tumours – there was much more to learn.
Researchers needed to understand the best combination of the three components, with a high proportion of ADC candidates not making it past clinical trial.
Tercel is leading a new study, supported by the Government’s Endeavour Fund, looking at new drugs, or “payloads” as she calls them, to incorporate into ADCs.
The majority of ADCs in clinical trial are based on just two classes of drugs which share the same mechanism of action – disrupting the microtubules inside cells that are essential for cell division.
“Interest is now shifting to exploring other classes of drugs that work by interacting with DNA,” Tercel said.
These were potentially better payloads as they could be extremely potent, could work against tumour cells whether they were dividing or not, and prove harder for tumour cells to develop resistance to.
“In the Auckland Cancer Society Research Centre we have a lot of experience designing and making compounds that interact with DNA, both as chemotherapeutics in their own right, and as ADC payloads,” she said.
“We have identified some particular structures that address known shortcomings in existing payloads and have a lot of potential for ADC use.”
Most of the research would be carried out by medicinal chemists creating new compounds in the lab.
“We already know the structures we want to target, so it’s a case of beginning with commercially available, small-molecule starting materials and working through perhaps 10 or 15 chemical conversions to slowly build up the target structures.”
At each step, the team would have to characterise the products to ensure they offered what they sought, before they were finally tested against lab-grown human tumour cells.
“For the most active new payloads, we’ll also incorporate a linker that can be used to connect our new payloads to an antibody,” Tercel said.
In the short term, the team’s focus would be on filing patents to protect the new compounds and make them attractive development options.
“Currently, pharmaceutical ADC development is not being undertaken in New Zealand, so it’s likely that we will proceed to commercialisation via licensing deals with any one of the many international pharmaceutical companies that are bringing ADCs to clinical trial.
“Ultimately we’d love to see our new compounds incorporated into ADCs that can bring benefit to cancer patients.”
Source: NZ Herald