MICA: Well-characterised monoclonal antibody-photosensitiser conjugates for the treatment of head and neck cancer

The project involves developing a novel treatment for head and neck cancer. Head and neck cancer represent a number of different diseases including oral cancers and cancers of the oesophagus and larynx. Latest figures show that more than 16,000 cases of these cancers are diagnosed annually in the UK. Current treatments for head and neck cancer can lead to significant loss of quality of life through loss of speech, difficulties eating and drinking and disfigurement. The treatment we propose here, Photodynamic Therapy (PDT), is much milder than surgery or radiotherapy and consists of administering a dye which localises in the tumour. Visible light, without heat, is used to activate the dye inside the cancer and this causes the release of a toxic form of oxygen (singlet oxygen). Singlet oxygen has a very short sphere of activity and if it does not react with a cancer cell component it returns to the normal, non-toxic form of oxygen. If sufficient singlet oxygen is generated within the tumour the cancer can be destroyed. Preliminary results have shown that a monoclonal antibody that targets head and neck cancer can be loaded with PDT dyes to deliver a high dose, and that this has been effective in model systems. We plan, during this project, to accumulate sufficient data to begin a clinical trial of this new treatment for head and neck cancer.

The proposal involves a translational study of novel photosensitiser-monoclonal antibody conjugates for targeted treatment of cancer using photodynamic therapy (PDT). The targeted conjugates will be tested in a clinically relevant animal model of head and neck cancer which is a key clinical application for PDT. A clinically tested human anti-angiogenic antibody available will be used, SIP(L19), which binds to the extra domain B (EDB) of fibronectin. This peptide is undetectable in plasma and normal tissues, but over-expressed on neovasculature of many solid tumours. Therefore SIP(L19) photosensitiser conjugates will exert their effect primarily by destruction of tumour vasculature. Vasculature targeting is likely to be considerably more effective compared to tumour cell targeting, due to the accessibility of the antigen to blood borne antibody conjugates, and because destruction of one blood vessel kills many thousands of tumour cells.

The key objectives are to optimise a new generation of well characterised photosensitser-antibody conjugates incorporating regioselective chemistry, and to demonstrate selective tumour destruction. Previous work on photosensitiser-antibody conjugates has employed coupling via lysine residues giving an average number of photosensitisers distributed randomly on the antibody surface, including the binding region. In contrast, we have recently developed methodology to selectively attach precisely two photosensitisers to SIP(L19) in a region remote from the binding site, and shown that immunoreactivity and photodynamic activity are retained in cell models. Using modified linkers it should be possible to attach up to six photosensitisers per antibody which should improve therapeutic efficacy. In proof-of-principle in vivo studies, we have shown that a similar photosensitiser conjugated non-regioselectively to lysine residues of SIP(L19) can eradicate sub-cutaneous murine carcinomas.

Our research has the potential to deliver impact for a wide range of beneficiaries, including clinicians and their patients, biomedical scientists and the pharmaceutical industry, as well as the direct academic participants at UoH and UCL. The impact stems primarily from the improved design of targeted photoactivatable drugs for translation into minimally invasive therapy of solid tumours. The main focus is on head and neck cancer, where standard treatments have several drawbacks. Surgical excision of head and neck cancers together with radiotherapy are the standard options but carry the risk of high morbidity and nerve damage. Radiotherapy can lead to severe side-effects, eg to bone, preventing re-treatment, and chemotherapy is relatively ineffective for head and neck tumours. In the longer term the treatment should be applicable to other types of solid tumours, eg prostate cancer.

For the general public, benefits will include improved quality of life due to minimisation of traumatic scarring and loss of tissue, a minimally invasive treatment regime which can be applied multiple times with minimal toxicity or skin photosensitivity, and enhanced survival rates due to suppression of secondary tumour growth associated with the immune response raised by this type of therapy. Following completion of this translational study and licensing of the technology, clinical trials would be undertaken leading to marketing of the product within 5-7 years.

The economic impact would be be significant since post-treatment hospitalisation is considerably reduced compared to surgery, risk of bacterial infection is minimised, and reconstructive surgery is usually not required. It would enhance the quality of NHS healthcare and enable clinical staff to work more efficiently. This outcome will have an impact upon quality of life in the UK and increase the effectiveness of public healthcare.

The research will also have impact for the academic institutions involved, in that our work should produce intellectual property leading to revenue streams obtained from licensing opportunities. The academic beneficiaries would include scientists and academic clinicians who are seeking improved means of detecting and treating cancer. As well as being of direct benefit to researchers in the field of drug delivery, our research will also be of potential benefit to the academic community at large, who will gain from the knowledge obtained in these studies for other research endeavours.

In the pharmaceutical sector, biotherapeutics now comprise a significant proportion of all drugs on the market. Achieving efficient delivery to targeted tissues is a major challenge that can limit the therapeutic potential of otherwise promising clinical candidates, and may result in their abandonment, despite huge investments in their discovery and development. The development of synthetic methodologies that expand the scope of the antibody-targeted techniques will benefit the pharmaceutical industry. For companies in the UK, this would lead to a positive impact on economic performance and competitiveness in the global market place.

Finally, the researchers who will perform the proposed studies will benefit from the opportunities to participate in a multidisciplinary research project, with valuable training in a range of chemical and biological techniques. This will greatly enhance their ultimate employment prospects in either industrial or academic settings. As such, the project will constitute a long-term training investment in the researchers and the creative output of the UK