Targeted photodynamic therapy with multiply-loaded recombinant antibody fragments

Authors

  • Manpreet Bhatti,

    1. Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London, United Kingdom
    Search for more papers by this author
  • Gokhan Yahioglu,

    Corresponding author
    1. PhotoBiotics, 21 Wilson Street, London EC2M 2TD, United Kingdom
    2. Department of Chemistry, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London, United Kingdom
    • Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK
    Search for more papers by this author
  • Lionel R. Milgrom,

    1. PhotoBiotics, 21 Wilson Street, London EC2M 2TD, United Kingdom
    2. Department of Chemistry, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London, United Kingdom
    Search for more papers by this author
  • Mitla Garcia-Maya,

    1. Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London, United Kingdom
    Search for more papers by this author
  • Kerry A. Chester,

    1. Department of Oncology, Royal Free and University College Medical School, University College London, London, United Kingdom
    Search for more papers by this author
  • Mahendra P. Deonarain

    Corresponding author
    1. Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London, United Kingdom
    • Division of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK
    Search for more papers by this author
    • Fax: +44 207 594 4560.


Abstract

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. © 2007 Wiley-Liss, Inc.

Ancillary