Antibody-Directed Phototherapy (ADP)

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

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…Several in vitro studies confirmed the interest of Ab-PS conjugates in PDT [226,227]. In most cases, a lower effective dose of Ab-PS conjugate was able to induce a higher selective phototoxic effect compared to PS or Ab alone.…”

“…21.B) [227]. Antibody-based photosensitizer delivery may offer significant benefits over conventional PDT.…”

Emerging formats for next-generation antibody drug conjugates

“…BL22 (anti-CD22 disulphide-linked Fv-Psuedomonas exotoxin), which is in advanced clinical trials for hairy cell leukaemia [93]. Such ScFv based carriers have shown more promise as vehicles for photosensitsiers, which are light-activated drug payloads [94]. Deonarain and co-workers demonstrated tumour cures using an anti-HER2 scFv optimised for PDT conjugation in collaboration with Photobiotics [95], whereas Boyle and co-workers focussed on a lower payload loading using the higher affinity antibodies as described by the Neri group [96].…”

Targeted Photodynamic Therapy for Improved Lung Cancer Treatment

“…Some of the advantages seen in PIT, compared to conventional cancer treatment such as chemotherapy/chemo-immunotherapy, is that during laser activation of the Ab-PS conjugate there is cell specific cytotoxicity of cancerous cells sparing the surrounding healthy tissue. Additionally PIT is neither immunosuppressive nor does it have an affinity for rapidly dividing cells, making it less likely to develop treatment induced resistance due to neoplastic cells up regulating alternative or circumventive pathways commonly seen in chemotherapy [48].…”