MHRA research evaluates two different approaches to cancer therapies

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The report 'Antibody conjugates for targeted delivery of Toll-like receptor 9 agonist to the tumor tissue', published in the PLOS ONE journal, highlights MHRA research which showed that genetic engineering of antibodies used to activate and support the immune system against cancer leads to improvements in their reliability and effectiveness.

Antibodies provide the human body with a natural defence mechanism, activating the immune system to fight disease and infection. Monoclonal antibodies (MAbs) are developed in a laboratory to produce multiple copies of these naturally occurring antibodies and replicate their properties.

MAbs are an example of immunotherapy and can in some cases support the immune response against cancer. As tumours develop from normal cells in the body, immune cells may not always recognise them as harmful. MAbs are being developed that can specifically recognise cancer cells and once found, they send a signal to initiate a targeted immune response against them.

Researchers and healthcare professionals have also been successfully harnessing the immune system to target tumour cells in other ways using toll-like receptor (TLR) agonists.

TLR agonists activate the proteins in immune cells that detect signs of infection, which initiates a general, broad immune response.

These have been used effectively when treating skin and bladder cancer, but only when treatment is applied directly to the tumour so that an immune response is triggered at the tumour site.

However, not all cancers can be treated directly and if these treatments are administered through a method such as infusion, the immune response occurs throughout the body, causing side effects for patients. By combining these TLR agonists with MAbs specific to a certain cancer, they can target tumour sites more directly, containing the immune response and reducing side effects.

However, the ability of this combination to target tumour sites effectively can be inconsistent, which reduces the effectiveness of the treatment. Researchers at the MHRA aimed to identify whether specifying the site on the MAbs surface where it bound to the TLR agonist could improve the reliability of this combination to target cancer cells.

They combined a TLR9 agonist with the MAb 'trastuzumab', which is currently used to treat some types of breast, oesophageal and stomach cancer.

The researchers then compared the resulting immune response from both random and site-specific binding of the TLR9 agonist with trastuzumab.

The random method resulted in the TLR9 agonist occasionally binding to trastuzumab in locations near its antigen binding sites, which are used to bind to cancer cell proteins and signal an immune response. This obstructed the MAb from binding to cancer cell proteins, reducing the chance of an effective immune response being triggered.

In contrast, genetically engineering the MAb, so that the TLR9 agonist bound further away from antigen binding sites leaves the ability of the antibody to bind to the specific cancer cell proteins intact.

The results showed that an effective immune response was more consistent in the site-specific tests than those in the random tests.

This indicates that engineering the site at which the MAbs and TLR agonists bind increases the effectiveness of this type of treatment making it more reliable and more likely to cause fewer side effects for patients.

Dr Sandra S. Diebold, Principal Scientist in Immunotherapy & Biotherapeutics at the MHRA said:

Patients with cancer often undergo punishing treatments that can severely impact on their quality of life. Finding ways to more reliably activate the immune system to detect and target cancer cells is a crucial step towards ensuring that patients receive more effective treatments with fewer side effects.

While further research will be necessary to evidence the benefits of a site-specific approach, this study shows promise in achieving this aim for patients.

By adding to the body of evidence around methods for combining MAbs with TLR agonists, we hope to further support the development of safer and more effective cancer treatments."

Will Quince, Minister for Health and Secondary Care said:

More targeted treatments could mean better outcomes for patients, that's why we're investing in cutting edge cancer research for patients and working with scientists to develop effective treatment with fewer side effects.

We have also partnered with some of the best and brightest minds that created Covid vaccines to try to develop new cancer vaccines and are investing record amounts into exciting trials looking at ways of better treating >cancer."

Dr Henry Stennett, Research Information Manager at Cancer Research UK, said:

This study shows the power of precisely reengineering the immune system to unlock its ability to fight cancer.

Although more work is needed to translate these results to the clinic, we're excited to see scientists developing more effective and kinder treatment options for people with cancer.

Innovative new therapies based on research discoveries are critical to beating this disease."

Source:
Journal reference:

Corogeanu, D., et al. (2023). Antibody conjugates for targeted delivery of Toll-like receptor 9 agonist to the tumor tissue. PLOS ONE. doi.org/10.1371/journal.pone.0282831.

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