Targeted photodynamic therapy with multiply-loaded recombinant antibody fragments.
Current photodynamic therapy (PDT) of cancer is limited by inefficiencies involved in specifically targeting photosensitizers to tumors. Although antibodies are being explored as targeting vehicles, they present significant challenges, particularly in terms of pharmacokinetics and drug-coupling. We describe here a novel and effective system to covalently attach multiple photosensitizer molecules (both preclinical, pyropheophorbide-a and clinically approved, verteporfin photosensitizers) to single-chain Fvs. Further, we demonstrate that not only do the resulting photoimmunoconjugates retain photophysical functionality, they are more potent than either free photosensitizer, effectively killing tumor cells in vitro and in vivo. For example, treatment of human breast cancer xenografts with a photoimmunoconjugate comprising an anti-HER-2 scFv linked to 8-10 molecules of pyropheophorbide-a leads to significant tumor regression. These results give an insight into the important features that make scFvs good carriers for PDT drugs and provide proof of concept of our unique approach to targeted photodynamic therapy (tPDT). This promises to significantly improve on current photodynamic therapies for the treatment of cancer.
Bhatti
Manpreet
M
Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London, United Kingdom.
Yahioglu
Gokhan
G
Milgrom
Lionel R
LR
Garcia-Maya
Mitla
M
Chester
Kerry A
KA
Deonarain
Mahendra P
MP
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000008:administration & dosage* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D020893:Receptor, ErbB-3 / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics
D000951:Antigens, Neoplasm; D007128:Immunoglobulin Fragments; D017319:Photosensitizing Agents; D011994:Recombinant Proteins; D020893:Receptor, ErbB-3