Porphyrin modified trastuzumab improves efficacy of HER2 targeted photodynamic therapy of gastric cancer

Journal Article · Mon Jul 10 00:00:00 EDT 2017 · International Journal of Cancer

DOI:https://doi.org/10.1002/ijc.30844· OSTI ID:1631463

Korsak, Barbara ^[1]; Almeida, Gabriela M. ^[2]; Rocha, Sara ^[2]; Pereira, Carla ^[2]; Mendes, Nuno ^[2]; Osório, Hugo ^[3]; Pereira, Patrícia M. R. ^[4]; Rodrigues, João M. M. ^[4]; Schneider, Rudolf J. ^[5]; Sarmento, Bruno ^[6]; Tomé, João P. C. ^[7]; Oliveira, Carla ^[3]

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1. Instituto de Investigação e Inovação em Saúde‐ i3S, Universidade do Porto Portugal, Ipatimup, Institute of Molecular Pathology and Immunology at the University of Porto Porto Portugal, QOPNA and Department of Chemistry University of Aveiro Aveiro Portugal
2. Instituto de Investigação e Inovação em Saúde‐ i3S, Universidade do Porto Portugal, Ipatimup, Institute of Molecular Pathology and Immunology at the University of Porto Porto Portugal
3. Instituto de Investigação e Inovação em Saúde‐ i3S, Universidade do Porto Portugal, Ipatimup, Institute of Molecular Pathology and Immunology at the University of Porto Porto Portugal, Department of Pathology and Oncology Faculty of Medicine, University of Porto Porto Portugal
4. QOPNA and Department of Chemistry University of Aveiro Aveiro Portugal
5. Department of Analytical Chemistry Reference Materials, BAM Federal Institute for Materials Research and Testing Berlin Germany
6. Instituto de Investigação e Inovação em Saúde‐ i3S, Universidade do Porto Portugal, INEB, National Institute of Biomedical Engineering‐University of Porto Porto Portugal, Inovapotek Pharmaceutical Research and Development Porto Portugal, CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde and Instituto Universitário de Ciências da Saúde Gandra Portugal
7. QOPNA and Department of Chemistry University of Aveiro Aveiro Portugal, Department of Organic and Macromolecular Chemistry Ghent University Ghent Belgium, Departamento de Engenharia Química Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa Lisboa Portugal

Gastric cancer (GC) is the 3rd deadliest cancer worldwide, due to limited treatment options and late diagnosis. Human epidermal growth factor receptor‐2 (HER2) is overexpressed in ∼20% of GC cases and anti‐HER2 antibody trastuzumab in combination with conventional chemotherapy, is recognized as standard therapy for HER2‐positive metastatic GC. This strategy improves GC patients' survival by 2–3 months, however its optimal results in breast cancer indicate that GC survival may be improved. A new photoimmunoconjugate was developed by conjugating a porphyrin with trastuzumab (Trast:Porph) for targeted photodynamic therapy in HER2‐positive GC. Using mass spectrometry analysis, the lysine residues in the trastuzumab structure most prone for porphyrin conjugation were mapped. The in vitro data demonstrates that Trast:Porph specifically binds to HER2‐positive cells, accumulates intracellularly, co‐localizes with lysosomal marker LAMP1, and induces massive HER2‐positive cell death upon cellular irradiation. The high selectivity and cytotoxicity of Trast:Porph based photoimmunotherapy is confirmed in vivo in comparison with trastuzumab alone, using nude mice xenografted with a HER2‐positive GC cell line. In the setting of human disease, these data suggest that repetitive cycles of Trast:Porph photoimmunotherapy may be used as an improved treatment strategy in HER2‐positive GC patients.

• Sponsoring Organization: USDOE
• OSTI ID: 1631463
• Journal Information: International Journal of Cancer, Journal Name: International Journal of Cancer Journal Issue: 7 Vol. 141; ISSN 0020-7136
• Publisher: Wiley Blackwell (John Wiley & Sons)
• Country of Publication: United States
• Language: English