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Radiolabeled HER-2 Binding Affibody Molecules for Tumor Targeting

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Radiolabeled HER-2 Binding Affibody Molecules for Tumor Targeting Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 127 Radiolabeled HER-2 Binding Affibody Molecules for Tumor Targeting Preclinical Studies ANN-CHARLOTT STEFFEN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 UPPSALA ISBN 91-554-6503-X 2006 urn:nbn:se:uu:diva-6678 ! "#$% & ' ( & & ' ' )* & + ,- .' / /'- && 01- !- 230 4 ( && + & . . ( (- - - $5- !6 - - 748 "$0%%90!% 60:- 1 ' ' ' && ( - 4 ( ' ' & ' - . ( ( ( ' '- 7 ' ' && / ' '(' && & ' 230 ' ( / ' (( & & / - & ( / ' $%7 ' && & / 230 ( - 7 / ' / ' ' 230 ( ( && ( & ' - .' ; & ' && & ' (' ' - 0 0 & $ (' ' < / ' ' ; ( - .' ( && & ' && && / / ' ' && & ' ; - 7 / & ' ' (' ( ' ' && && ( - .' && / / ' ' ' 0 ( $$ - & / 230 ( ( ' $$ && - .' ' && / & && / ' ; ;- .' $$ && / /' & ' $$ / - . ' <( ' / / ( & $$ ( - .' ' ' ; & && & & ' & - 230 && $$ ( ( ( ' ( ( ! " # " $ % " & $ " $'( ' " " )!*+,-+ " = 01' && ! 78 $!%$0! ! 748 "$0%%90!% 60: # ### 0!!5> )' #?? --? @ A # ### 0!!5>, List of papers I Wikman M, Steffen AC, Gunneriusson E, Tolmachev V, Adams GP, Carlsson J, Ståhl S: Selection and characterization of HER2/neu-binding affibody ligands. Protein Engineering Design & Selection 2004, 17(5):455-462. II Steffen AC, Wikman M, Tolmachev V, Adams GP, Nilsson FY, Stahl S, Carlsson J: In Vitro Characterization of a Bivalent Anti- HER-2 Affibody with Potential for Radionuclide-Based Diagnos- tics. Cancer Biotherapy and Radiopharmaceuticals 2005, 20(3):239-248. III Steffen AC, Orlova A, Wikman M, Nilsson FY, Ståhl S, Adams GP, Tolmachev V, Carlsson J: Affibody mediated tumour target- ing of HER-2 expressing xenografts in mice. European Journal of Nuclear Medicine and Molecular Imaging 2006, In press IV Ekerljung L, Steffen AC, Carlsson J, Lennartsson J: Effects of HER2-binding Affibody Molecules on Intracellular Signaling Pathways. Tumor Biology 2006, vol 27, In press V Steffen AC, Göstring L, Tolmachev V, Carlsson J: Differences in 211 sensitivity for At-(ZHER2:4)2 treatment between three HER-2 overexpressing cell lines. Submitted to Radiation Research 2006 VI Steffen AC, Almqvist Y, Chyan MK, Lundqvist H, Tolmachev V, Wilbur DS, Carlsson J: Biodistribution and dose calculations for 211At labeled HER-2 binding affibody molecules. Manuscript, 2006 Reprints were made with permission from Oxford Journals (I), Mary Ann Liebert, Inc. Publishers (II), Springer Science and Business Media (III) and S. Karger AG, Basel (IV). Contents Introduction.....................................................................................................9 Cancer ........................................................................................................9 Cancer treatments today ........................................................................9 Experimental therapies ..........................................................................9 Cancer detection ..................................................................................10 Tumor targeting........................................................................................10 Molecular targets .................................................................................11 The EGF receptor family ................................................................11 The EGF receptor /HER-1..........................................................11 HER-2 / neu................................................................................12 HER-3 and HER-4......................................................................13 Signaling.....................................................................................13 Targeting agents ..................................................................................14 Antibodies.......................................................................................15 Antibody fragments.........................................................................17 Peptides...........................................................................................19 Affinity proteins..............................................................................19 Affibody molecules ....................................................................20 Selection systems ............................................................................21 Phage display..............................................................................21 Other systems .............................................................................23 Therapeutic/visualizing moieties .........................................................23 Therapy ...........................................................................................23 Radionuclides .............................................................................23 Toxins.........................................................................................25 Cancer drugs...............................................................................25 Visualization ...................................................................................25 The present study ..........................................................................................27 Selection of HER-2 binding affibody molecules (I & II).........................27 Biacore testing (I & II) .............................................................................28 125I labeled HER-2 binding affibody molecules .......................................29 Cellular testing (I & II)........................................................................29 Specific binding / epitope comparison............................................29 Cellular internalization and retention..............................................30 Cellular retention.............................................................................31 Biodistribution in mice (III).................................................................32 Gamma camera imaging (III) ..............................................................34 Autoradiography/immunohistochemistry (III) ....................................35 Cellular effects of the HER-2 binding affibody molecules (IV) ..............35 211At labeled HER-2 binding affibody molecules ....................................37 In vitro therapy (V)..............................................................................38 Biodistribution (VI) .............................................................................43 Other ongoing studies with tumor targeting affibody molecules..................47 Summary.......................................................................................................48 Future studies................................................................................................50 Acknowledgments.........................................................................................51 References.....................................................................................................54 Abbreviations AHNP Anti-HER-2/neu peptide CDR Complementarity determining region CPM Counts per minute DAG Diacylglycerol DNA Deoxyribonucleic nucleic acid ECD Extracellular domain EGF Epidermal growth factor EGFR Epidermal growth factor receptor Erk Extracellular regulated kinase Fab Antigen-binding fragment FACS Fluorescence activated cell sorting Fv Variable fragment GDP Guanosine diphosphate GTP Guanosine triphosphate Gy Gray HAMA Human anti-mouse antibody HER Human EGF receptor i.p. Intraperitoneally i.v. Intravenously kBq Kilobequerel KD Dissociation equilibrium constant kDa Kilodalton kon Association rate constant koff Dissociation rate constant LET Linear energy transfer MAb Monoclonal antibody MAPK Mitogen-activated protein kinase p.i. Post-injection PCR Polymerase chain reaction PDK Phosphatidylinositol-dependent protein kinase PET Positron emission tomography PI(3)K Phosphatidylinositol-3-OH kinase PIP2 Phosphatidylinositol 4,5-biphosphate PIP3 Phosphatidylinositol 3,4,5-triphosphate PKC Protein kinase C PLC phospholipase C PAB N-succinimidyl-para-astatobenzoate PIB N-succinimidyl-para-iodobenzoate PSA Prostate specific antigen RBE Relative biological effectiveness RNA Ribonucleic acid s.c. Subcutaneously scFv Single-chain Fv SD Standard deviation SELEX Systematic evolution of ligands by exponential enrichment SPECT Single photon emission computed tomography SPMB N-succinimidyl-para-(tri-methylstannyl)benzoate TGF Transforming growth factor Introduction Cancer Cancer is one of the most common diseases in the western world today. Ap- proximately one out of three people will receive a cancer diagnose in their life time, and cancer is responsible for about 23% of all deaths. That makes cancer the second most common cause of death, after cardiovascular disease, in the western world. The number of diagnosed cases has dramatically in- creased during the last decades. The aging population is believed to be re- sponsible for a large part of the increase, but taking this into account, there has still been an increase in diagnosed cases [1]. The mortality has, during the same time, decreased somewhat, and the expectation
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