Abstract
Photodynamic therapy (PDT) is a clinically-approved but rather under-exploited treatment modality for cancer and pre-cancerous superficial lesions. It utilises a cold laser or LED to activate a photochemical reaction between a light activated drug (photosensitiser-drug) and oxygen to generate cytotoxic oxygen species. These free radical species damage cellular components leading to cell death. Despite its benefits, the complexity, limited potency and side effects of PDT have led to poor general usage. However, the research area is very active with an increasing understanding of PDT-related cell biology, photophysics and significant progress in molecular targeting of disease. Monoclonal antibody therapy is maturing and the next wave of antibody therapies includes antibody-drug conjugates (ADCs), which promise to be more potent and curable. These developments could lift antibody-directed phototherapy (ADP) to success. ADP promises to increase specificity and potency and improve drug pharmacokinetics, thus delivering better PDT drugs whilst retaining its other benefits. Whole antibody conjugates with first generation ADP-drugs displayed problems with aggregation, poor pharmacokinetics and loss of immuno-reactivity. However, these early ADP-drugs still showed improved selectivity and potency. Improved PS-drug chemistry and a variety of conjugation strategies have led to improved ADP-drugs with retained antibody and PS-drug function. More recently, recombinant antibody fragments have been used to deliver ADP-drugs with superior drug loading, more favourable pharmacokinetics, enhanced potency and target cell selectivity. These improvements offer a promise of better quality PDT drugs.
Highlights
Many head & neck cancers can be treated using PS-drugs such as Foscan® that is championed by some in this field [20,21,22] over classical treatments options as it is: (i) more cost-effective; (ii) has superior cosmetic outcome with equivalent or improved results; (iii) provides the chance of a cure for patients who would otherwise have been unfit for treatment or for those who have previously failed with radiotherapy, surgery or systemic chemotherapy
Purer second generation photosensitisers were subsequently developed alongside an improvement in chemical syntheses techniques and many are currently in clinical use. These PS are mostly based on porphyrins, chlorins or bacteriochlorins, with their pharmacokinetic, photodynamic and spectral properties varying due to differences in their chemical structures (Figure 3)
In between the first steps and today, significant scientific developments have helped shaped the field of Antibody-Directed Phototherapy (ADP)-drugs: The increase in new synthetic and/or chemically modified PS-drugs has improved alongside a growth in the understanding of the important aspects for effective Photodynamic therapy (PDT)
Summary
Antibody targeting of cancer has shown many clinical and commercial successes and continues to do so [1,2,3,4,5]. Patients exhibiting resistance still retain high tumour surface HER2 expression levels, resistance instead is thought to be due to subsequent changes in oncogenic signaling which circumvent the drug action [9] This lack of HER2 receptor down-regulation has led to the development of several anti-HER2 antibody-conjugates which can continually deliver cytotoxins directly to the tumour. Mylotarg was approved in 2,000 for acute myeloid leukaemia but was withdrawn in June 2010 after post-approval clinical studies [11] and possibly poor sales in competition with unconjugated antibodies This has begun to change; alongside the potency ‘gap’ left by native antibodies we have better characterized and validated target antigens, human-like or fully human antibodies and their recombinant fragments, improved protein-chemical conjugation technologies and more potent drugs. Many head & neck cancers can be treated using PS-drugs such as Foscan® that is championed by some in this field [20,21,22] over classical treatments options as it is: (i) more cost-effective; (ii) has superior cosmetic outcome with equivalent or improved results; (iii) provides the chance of a cure for patients who would otherwise have been unfit for treatment or for those who have previously failed with radiotherapy, surgery or systemic chemotherapy
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