Antibody‐Targeted Photodynamic Therapy

Abstract

Photodynamic therapy (PDT) is a clinically approved treatment modality for cancer and superficial lesions. It harnesses the photochemical reaction between the lightsensitizing drug and oxygen to generate cytotoxic reactive oxygen species which destroy cells. Although with many benefits, its complexity, lack of potency and side effects 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 leading to the next generation of PDT.Monoclonal antibody therapy is very successful and the next wave of monoclonal antibody therapies-antibody-drug conjugates (ADCs) could also sweep antibodytargeted PDT to success. Antibody-targeted PDT 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 photosensitisers displayed problems with aggregation, poor pharmacokinetics and loss of immuno-reactivity. However, these early photo-immunoconjugates still showed improved selectivity and potency. Improved photosensitiser chemistry and a variety of conjugation strategies have led to improved photo-immunoconjugates with retained antibody and photosensitiser function. More recently, recombinant antibody fragments have been used to form photo-immunoconjugates with good drug loading, more favourable pharmacokinetics, enhanced potency and target cell selectivity. non-curative. This is particularly true for solid cancers which have many more barriers to overcome compared to haematological cancers. As an example, trastuzumab (a MAb recognizing human epidermal growth factor receptor-2, HER2) (Herceptin ® ) is a successful breast cancer drug which extends survival by around 5-7 months [Nahta et al, 2006]. It works by a variety of mechanisms, mainly involving oncogenic signaling modulation. However, most patients do not respond or eventually become resistant, due to further defects in signaling which circumvents the drug action [Nahta et al, 2006]. Many of these still express the HER2 receptor target which has led to the development of antibody-conjugates which act directly by delivering a cytotoxin. Conjugates with radio-isotopes (radio-immunotherapy, RIT), toxins (immunotoxins) and drugs (Antibody-drug conjugates, ADCs) have in fact been around since the 1960s and 1970s [Alley et al, 2010; Hughes, 2010]. These have failed for many reasons [Hughes, 2010], but the 'gap' left by native MAbs and recent developments in fusion and conjugation technology has seen a re-birth in antibody conjugates. Antibody-drug conjugates. Many parallels can be drawn between antibody conjugates with photosensitisers (photo-immunoconjugates, PICs) and ADCs. As mentioned already, ADCs have been around for over 30 years but there is only one approved clinical agent. Mylotarg ® -an anti-CD33 MAb conjugated to calicheamycin that was approved in 2000 for acute myeloid leukaemia but was ...

Photodynamic Tumor Eradication With a Novel Targetable Photosensitizer: Strong Vascular Effects and Dependence on Treatment Repetition Versus Potentiation

“…Putting these results in perspective, it will be necessary to judge all targeted PDT studies more critically, since many studies may have underestimated or overlooked nonspecific vascular effects. (10,28,31) The question remains whether a passively targeted PS may be better in the end, at least for some applications, since we have shown herein that repeated Ac-sPPp PDT provides the most reliable eradication of recurrent A-431 tumors. In ongoing work, we are finding that repeated Ac-sPPp PDT can also be quite effective for controlling other tumors.…”

“…Although extending the time between PS and light administrations improved PIC specificity, better specificity came at the cost of overall reduced efficacy. Putting these results in perspective, it will be necessary to judge all targeted PDT studies more critically, since many studies may have underestimated or overlooked nonspecific vascular effects …”

“…While there have been a large number of in vitro studies demonstrating the feasibility of PIC-targeted PDT, there have only been a handful of in vivo studies, and many confounding issues remain unanswered or inadequately addressed. (10) In particular, the hydrophobicity of many PSs and their aggregation in aqueous solutions have made it difficult to produce optimal PICs. (4,11) Moreover, no in vivo studies to date have definitively demonstrated that PICs offer a decisive advantage over passively targeted PSs.…”

“…Despite increasing interest in these sorts of approaches for potentiating PDT and improving target specificity, in vivo studies have been relatively limited. While there have been a large number of in vitro studies demonstrating the feasibility of PIC‐targeted PDT, there have only been a handful of in vivo studies, and many confounding issues remain unanswered or inadequately addressed . In particular, the hydrophobicity of many PSs and their aggregation in aqueous solutions have made it difficult to produce optimal PICs .…”

Synthesis and Applications of Porphyrin-Biomacromolecule Conjugates

“…Further, Németh et al, in 1998 again used the same carbodiimide conjugation strategy to generate a-Thy-1-hematoporphyrin antibody targeting Thy-l antigen in T lymphocytes to show the selective killing of T lymphocytes by the phototoxic conjugate upon irradiation ( Berki and Németh, 1998 ). Other groups have also used similar carboxyl modified commercially available photosensitizers, and have performed amide coupling with antibodies for targeted tumor cell killing ( Roberts et al, 1987 ; Martsev et al, 1995 ; Linares et al, 2004 ; Deonarain et al, 2012 ; Konopińska et al, 2015 ). Various polymeric linkers (polyvinyl alcohol, polyglutamic acid, dextran, and polylysine) have also been incorporated to generate photoimmunoconjugates ( Bullous et al, 2011 ).…”