Anticorpo Trastuzumab modificado com porfirina aumenta a eficácia da terapia anti-HER2 em cancro gástrico quando usado como terapia fotodinâmica dirigida

Uma colaboração entre investigadores do Ipatimup/i3S, INEB/i3S e Universidade de Aveiro permitiu desenvolver um novo fotoimunoconjugado de Porfirina e Trastuzumab que elimina específica e eficazmente células de cancro gástrico que expressam a proteína HER2. Este resultado foi obtido após tratamentos in vitro e in vivo e comparado com tratamento apenas com trastuzumab. Este estudo sugere que na doença humana, ciclos repetidos de tratamento com este tipo de fotoimunoterapia podem melhorar o tratamento de doentes com cancros gástricos HER2 positivos.

Autores e afiliações:

Barbara Korsak,^1,2,3#§ Gabriela M. Almeida,^1,2# Sara Rocha^,1,2 Carla Pereira,^1,2 Nuno Mendes,^1,2 Hugo Osório,^1,2,4 Patrícia M. R. Pereira,³ João M. M. Rodrigues,³ Rudolf J. Schneider,⁵ Bruno Sarmento,^1,6,7,8 João P. C. Tomé,^3,9,10* Carla Oliveira^1,2,4*

¹Instituto de Investigação e Inovação em Saúde- i3S, Universidade do Porto, Portugal

²Ipatimup, Institute of Molecular Pathology and Immunology at the University of Porto, Porto, Portugal

³QOPNA and Department of Chemistry, University of Aveiro, Aveiro, Portugal

⁴Faculty of Medicine, University of Porto, Portugal

⁵BAM Federal Institute for Materials Research and Testing, Berlin, Germany

⁶INEB, National Institute of Biomedical Engineering-University of Porto, Porto, Portugal

⁷Inovapotek Pharmaceutical Research and Development, Porto, Portugal

⁸CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde & Instituto Universitário de Ciências da Saúde, Gandra, Portugal

⁹Department of Organic and Macromolecular Chemistry, Ghent University, Ghent, Belgium

¹⁰Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal

^#B. Korsak and G.M. Almeida contributed equally for this work

*Shared senior co-authorship

§Current address: Heidelberg Pharma GmbH, Schriesheimer Str. 101, 68526 Ladenburg, Germany.

Abstract: 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.

Revista: International Journal of Cancer

Link: http://onlinelibrary.wiley.com/doi/10.1002/ijc.30844/full