‘Death by garbage’ – Improving the effectiveness of antibody treatment

How can we make antibody treatment more effective?

It’s an exciting headline – “Potent cancer drug hopes raised” – but what’s the real story behind it?

This is research from scientists in Manchester, Southampton and Latvia, funded by Cancer Research UK, Leukaemia Research, the AICR, Tenovus, and the ECMC network and published in the Journal of Clinical Investigation.

In their paper, the researchers have found that some types of antibody can kill cancer cells in a new and unexpected way – by causing their internal ‘rubbish bins’ to overflow, literally flooding them with toxic ‘garbage’.

The results raise hopes for more effective treatments in the future – but we need to be careful not to get too excited, because there’s still a long way to go.

Antibody-based cancer drugs
Antibodies are proteins produced by the immune system, with the ability to recognise and stick to other proteins with a high degree of accuracy.  In the body, they are used to alert the immune system to the presence of invading bacteria or viruses.

In recent years, progress has been made in developing antibody-based treatments for cancer, such as the lymphoma drugs Rituximab and Herceptin.  Some of these treatments are extremely effective. For example, Rituximab has made a significant improvement to survival from non-Hodgkin lymphoma.

Although they work in a variety of ways, a common theme is that many antibody drugs alert the immune system to the presence of cancer.

Similar drugs, different effects

In theory, such antibody-based drugs should be similarly effective at killing cancer cells. But – intriguingly –  some are significantly more potent than others, with a more powerful cell-killing effect.

A research team led by Dr Mark Cragg and Professor Tim Illidge, wanted to find out the reason for this difference, because it could have a significant impact on the development of future antibody treatments.

So the researchers tested two experimental antibody drugs on human leukaemia and lymphoma cells that had been grown in the lab – tositumomab (also known as Bexxar) and one called L243.  These antibodies were chosen because they’d previously been shown to be particularly potent compared with other similar drugs including Rituximab.

The team  discovered that the antibodies caused the cancer cells to clump together and rapidly die, but in a most unexpected way – by flooding them with garbage.

Toxic overflow
Like any well-run city, a cell depends on efficient waste disposal to maintain a healthy environment. Inside the cell, waste products are kept within ‘waste disposal units’ called lysosomes. These are carefully sealed, to prevent their toxic contents from damaging important proteins and DNA within the cell.

When the cancer cells were treated with the antibodies, the researchers found that the lysosomes within them were literally exploding, pouring their contents out into the cells and causing rapid death.  Imagine a toxic waste swamp flooding a city, and you’ll have a pretty good idea of what’s going on.

Next steps
The fact that the Bexxar and L243 cause this dramatic effect explains why they are more potent than other antibodies (such as Rituximab) that alert the immune system but don’t directly cause cell death.

This knowledge is vital for researchers who are currently developing and testing antibody-based cancer treatments that direct the immune system to kill the tumour.  It suggests that the most potent antibodies will be those that can spark the ‘death by garbage’ response in cancer cells.

And there is another important twist. Many chemotherapy drugs work by tricking cancer cells into committing suicide by a completely different process, called ‘apoptosis’. But during treatment, tumours often evolve to turn off their apoptosis machinery, cheating death and leading to drug resistance.

But because these new antibodies provoke a different method of cell death, they may be useful for treating patients whose tumours have become resistant to chemo.

But it’s important not to get too excited just yet. Although these results are scientifically interesting – and will doubtless inform the development of more potent antibody treatments – there’s still a lot more work to be done.

Kat

Reference:
Ivanov, A. et al (2009). Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells Journal of Clinical Investigation DOI: 10.1172/JCI37884