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[Lu-177]pertuzumab: Experimental therapy of HER-2-expressing xenografts
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
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2007 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 1, 326-331 p.Article in journal (Refereed) Published
Abstract [en]

Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled with the low-energy beta emitter Lu-177, might be a candidate for targeted radiotherapy of disseminated HER-2-positive micrometastases. The radiolabeled antibody [Lu-177]pertuzumab showed favorable targeting properties in BALB/c (nu/nu) mice with HER-2-overexpressing xenografts. The absorbed dose in tumors was more than five times higher than the absorbed dose in blood and more than seven times the absorbed dose in any other normal organ. Experimental therapy showed that [Lu-177]pertuzumab delayed tumor progression compared with controls (no treatment, P < 0.0001; nonlabeled pertuzumab antibody, P < 0.0001; and Lu-177-labeled irrelevant antibody, P < 0.01). No adverse side effects of the treatment could be detected. Thus, the experimental results support the planning of clinical studies applying [Lu-177]pertuzumab for therapy.

Place, publisher, year, edition, pages
2007. Vol. 67, no 1, 326-331 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94334DOI: 10.1158/0008-5472.CAN-06-2363ISI: 000243320000041PubMedID: 17210714OAI: oai:DiVA.org:uu-94334DiVA: diva2:168149
Available from: 2006-04-20 Created: 2006-04-20 Last updated: 2011-02-17Bibliographically approved
In thesis
1. Antibody Mediated Radionuclide Targeting of HER-2 for Cancer Diagnostics and Therapy: Preclinical Studies
Open this publication in new window or tab >>Antibody Mediated Radionuclide Targeting of HER-2 for Cancer Diagnostics and Therapy: Preclinical Studies
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Antikroppsmedierad målsökning av radionuklider till HER-2 för cancerdiagnostik och terapi : Prekliniska studier
Abstract [en]

Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases.

Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of 125I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking 125I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter 76Br by using NBI. Furthermore, it is shown that cellular uptake of 125I can be modified by stimulating EGFR (HER-1) with EGF.

When labelled with the alpha emitter 211At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab.

Pertuzumab was radiolabelled with the low energy beta emitter 177Lu without losing affinity or immunocompetence. [177Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line.

In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with 177Lu, show promise as TRT agents.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 140
Keyword
Molecular medicine, Neoplasm Antibodies, Targeted Radiotherapy, Radionuclide Imaging, Molekylärmedicin
Identifiers
urn:nbn:se:uu:diva-6798 (URN)91-554-6535-8 (ISBN)
Public defence
2006-05-13, Rudbeck hall, Rudbeck laboratory, Dag Hammarskölds väg 20, Uppsala, 09:15
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Supervisors
Available from: 2006-04-20 Created: 2006-04-20 Last updated: 2011-02-17Bibliographically approved

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