title: Photochemical activation of the recombinant HER2-targeted fusion toxin MH3-B1/rGel; Impact of HER2 expression on treatment outcome.
abstract: HER2 is overexpressed in 20-30% of breast tumors and is associated with aggressiveness and increased risk of recurrence and death. The HER2 protein is internalized as a part of its activity, and may therefore be utilized as a target for the specific intracellular delivery of drugs. Photochemical internalization (PCI) is a novel technology now undergoing clinical evaluation for its ability to improve the release into the cytosol of drugs entrapped in the endo/lysosomal compartment. PCI employs an amphiphilic photosensitizer which localizes in the membranes of endo/lysosomes. Subsequent light exposure (visible light) causes destabilization of the endo/lysosomal membranes. PCI has been proven highly effective for improving the cytosolic delivery of targeted toxins based on type I ribosome inactivating protein toxins such as gelonin. We examined the impact of the level of target antigen expression on PCI efficacy. Four human breast cancer cell lines (MDA-MB-231, BT-20, Zr-75-1 and SK-BR-3) covering a wide range of HER2 expression were included in the present study. PCI of the HER2-targeted fusion toxin MH3-B1/rGel was found to be highly effective in all four cell lines. The increase in PCI-mediated efficacy was not directly correlated with the cellular levels of HER2 as assessed by western blots, the overall uptake of MH3-B1/rGel as measured by flow cytometry, the amount of MH3-B1/rGel localized to endo/lysosomes assessed by confocal microscopy or the cell sensitivity to the photochemical treatment itself (photosensitizer and light without MH3-B1/rGel). However, correcting the PCI efficacy for the baseline cellular sensitivity to rGel revealed a linear correlation (R(2)=0.80) with HER2 expression. The present report therefore concludes the cellular sensitivity to the toxin as an important parameter for PCI efficacy and also indicates PCI of a HER2-targeted fusion toxin as an attractive treatment alternative for breast cancer patients with both HER2-low and -high expression.
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway.
authors.forename: Bente
authors.initials: B
authors.lastname: Bull-Hansen
authors.affiliation: Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Berg
authors.affiliation: Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway.
authors.forename: Ellen
authors.initials: E
authors.lastname: Skarpen
authors.affiliation: Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenblum
authors.affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Norway. Electronic address: anette.weyergang@rr-research.no.
authors.forename: Anette
authors.initials: A
authors.lastname: Weyergang
mesh_terms: D000906:Antibodies / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D008027:Light; D055668:Photochemical Processes; D017319:Photosensitizing Agents / Q000008:administration & dosage; D011166:Porphyrins / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D054789:Ribosome Inactivating Proteins, Type 1 / Q000008:administration & dosage*
chemical_list: D000906:Antibodies; D000922:Immunotoxins; D017319:Photosensitizing Agents; D011166:Porphyrins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C559366:meso-tetraphenyl chlorin disulphonate
keywords: Breast cancer; HER2/neu/ErbB2; Immunotoxin; Photochemical internalization; Photodynamic; Triple negative breast cancer