Therapeutic Antibody Programme

Lead researchers: Prof Max Crispin, Prof Steve Beers, Dr Charlie Birts

Co-investigators: Hannah Smith, Dr John Butler, Lydia Doherty, Anil Chand, Abi Sudol

Location: University of Southampton

Dates:  Jan 2018 – Dec 2028     Status: In progress

Funding: £2,338,000

Research Theme: Therapies, Prevention

Aims

Against Breast Cancer’s first programme grant will support innovative research into the development of new antibody therapies for secondary breast cancer. The programme will focus on developing antibody-based therapies and understanding how they work within the complex tumour microenvironment. As a 10-year programme the research focus will develop and evolve over time but the general programme goals include:

• Developing novel derivatives of approved antibody therapies through antibody engineering.
• Enhancing understanding of glycan changes in metastatic cancer and how they can be targeted in antibody therapy.
• Understanding the impact of diet and lifestyle on the tumour microenvironment, associated breast cancer metastasis, and the implications for antibody therapies.

Background

Immunotherapy is a treatment that uses the body’s own immune system to help fight cancer, either by stopping or slowing the growth of cancer cells, preventing the cancer cells spreading, or helping the immune system destroy cancer cells. The most common forms of immunotherapy are monoclonal antibodies. These bind to a specific target (antigen) found on cancer cells and then recruit immune cells to destroy the cell the antibody has bound to.

Limitations to monoclonal antibody treatment include patients developing drug resistance, failing to respond to treatment or the treatment not killing the cancer cells sufficiently. Immunotherapy treatments rely on being able to distinguish cancer cells from healthy cells and this requires careful selection of the antibody target to reduce any potential side effects.

This Therapeutic Antibody programme principally focuses on ABC’s research theme of ‘Therapies’ using antibody engineering, which involves altering different regions of the antibody to change how it binds to target antigens or recruits immune cells.

In addition, the programme also aims to develop our immunotherapy research activities in the theme of ‘Prevention’ by understanding the impact of diet and lifestyle on the tumour microenvironment. There is growing evidence that there are underlying biological and immunological mechanisms that drive the association between diet, lifestyle and breast cancer metastasis. Importantly, diet and lifestyle can influence patient responses to antibody therapy and the programme ultimately aims to design new, more effective therapies.

Enhancing drugs: Engineering therapeutic antibodies

Therapeutic monoclonal antibodies have emerged as a powerful class of drug treatment against metastatic breast cancer. They often target particular surface proteins that are over expressed on cancer cells. One example is Herceptin (Trastuzumab) which is used to treat breast cancers that express human epidermal growth factor receptor 2 (HER2).

An important mechanism of action of anti-HER2 therapy is the recruitment of immune cells that then act to kill the cancer cell. However, one limitation of antibody treatment is that sometimes not all the cancer cells are sufficiently killed.

Immune cells are recruited via a part of the antibody called the Fc domain and different types of Fc domains can recruit specific immune cells with differing functions. The common antibody Fc domain format IgG1, that is found in many antibody therapies, recruits natural killer (NK) cells and cytotoxic T Cells.

Prof Crispin and his team want to exploit the different recruiting properties of antibodies. They hope to engineer new antibodies that broaden the immune cell recruiting properties beyond what a natural antibody could achieve, and ultimately, to develop improved antibody immunotherapy for patients.

Diet & Lifestyle: Impact of tumour microenvironment on therapeutic antibodies

Diet and lifestyle, and associated obesity levels, have an impact on metastasis and on the effectiveness of antibody therapies. Almost a third of breast cancer patients will go on to develop metastatic disease and further understanding of this process and its impact on therapy is a key goal of the programme. The team will explore how diet and lifestyle factors and obesity can influence the behaviour of immune cells and cancer cells during the progression of metastasis. Obesity alters the type and function of immune cells within the breast, creating long term (chronic) inflammation. This increases the risk of breast cancer metastasis. Obese patients also have a poorer response to immunotherapies suggesting that immune cell response is suppressed.

Prof Crispin has brought in the expertise of Prof. Steve Beers and Dr Charlie Birts, based at Southampton’s Centre of Cancer Immunology, and together they want to understand at the molecular level the impact of obesity on the tumour microenvironment. In particular, they are investigating how obesity impacts the immune cells that surround cancerous cells. The team are also utilising technologies developed within the ABC Discover programme to dissect the fine molecular features of the cancer cells.

Overall, this research theme unites the long-standing focus of Against Breast Cancer on the impact of diet and lifestyle on secondary breast cancer with the understanding of how effectiveness of therapeutic antibodies varies amongst diverse patients.

Potential benefit for patients

Antibody engineering may offer the potential for improved therapeutics, including increased specificity so fewer side effects are experienced, and enhanced cancer-killing ability to improve patient responses and long-term survival.

Furthermore, diet and lifestyle can impact the effectiveness of therapies for secondary breast cancer. By understanding how obesity influences the tumour microenvironment, there would be a route to developing new therapies designed to be more effective in traditionally lower responding patient groups.

Publications

Through the barricades: overcoming the barriers to effective antibody-based cancer therapeutics. Dalziel M, Beers SA, Cragg MS, Crispin M. Glycobiology. 2018 Sep 1;28(9):697-712.

Improving Antibody-Based Cancer Therapeutics Through Glycan Engineering. Xiaojie Yu, Michael J E Marshall, Mark S Cragg, Max Crispin. BioDrugs. 2017 Jun;31(3):151-166

Immune recruitment or suppression by glycan engineering of endogenous and therapeutic antibodies Le, N. P., T. A. Bowden, W. B. Struwe and M. Crispin (2016) Biochim Biophys Acta 1860 (8): 1655-1668 https://www.sciencedirect.com/science/article/pii/S0304416516301210 

Glycolysis, via NADH-dependent dimerisation of CtBPs, regulates hypoxia-induced expression of CAIX and stem-like breast cancer cell survival. Mira Kreuzer, A. Banerjee, Charles N. Birts, M. Darley, A. Tavassoli, M. Ivan, and Jeremy P. Blaydes. FEBS Letters 03 July 2020 

p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators. Charles N. Birts1,2, Arindam Banerjee1, Matthew Darley1, Charles R. Dunlop1, Sarah Nelson1, Sharandip K. Nijjar3, Rachel Parker1, Jonathan West1,2, Ali Tavassoli2,3, Matthew J. J. Rose-Zerilli1,2, and Jeremy P. Blaydes1,2 et al. Science Signaling 05 May 2020: Vol. 13, Issue 630, eaau9529 DOI: 10.1126/scisignal.aau9529

Signature of Antibody Domain Exchange by Native Mass Spectrometry and Collision-Induced Unfolding. Yasunori Watanabe, Snezana Vasiljevic, Joel D Allen, Gemma E Seabright, Helen M E Duyvesteyn, Katie J Doores, Max Crispin, Weston B Struwe. Anal Chem. 2018 Jun 19;90(12):7325-7331.

TNF receptor agonists induce distinct receptor clusters to mediate differential agonistic activity. Yu X, James S, Felce JH, Kellermayer B, Johnston DA, Chan HTC, Penfold CA, Kim J, Inzhelevskaya T, Mockridge CI, Watanabe Y, Crispin M, French RR, Duriez PJ, Douglas LR, Glennie MJ, Cragg MS. Commun Biol. 2021 Jun 23;4(1):772. doi: 10.1038/s42003-021-02309-5.