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Doctoral Thesis Hofstrom 2013 Camilla Hofström ISBN 978-91-7501-613-9 TRITA-BIO Report 2013:2 ISSN 1654-2312 Engineering of Affibody molecules for Radionuclide Engineering of affibody m Engineering moleculesfor radionuclide Molecular Imaging and Intracellular Targeting Camilla Hofström olecular olecular imaging and i and imaging ntracellular t argeting Doctoral thesis in Biotechnology KtH 2013 KtH stockholm, sweden 2013 www.kth.se Engineering of Affibody molecules for Radionuclide Molecular Imaging and Intracellular Targeting Camilla Hofström Royal Institute of Technology School of Biotechnology Stockholm 2013 © Camilla Hofström Stockholm 2013 Royal Institute of Technology School of Biotechnology AlbaNova University Center SE-106 91 Stockholm Sweden Printed by Universitetsservice US-AB Drottning Kristinas väg 53B SE-100 44 Stockholm Sweden ISBN 978-91-7501-613-9 TRITA-BIO Report 2013:2 ISSN 1654-2312 III ______________________________________________________________________________ Camilla Hofström (2013): Engineering of Affibody molecules for Radionuclide Molecular Imaging and Intracellular Targeting. School of Biotechnology, Royal Institute of Technology (KTH), Stockholm, Sweden Abstract Affibody molecules are small (-7 kDa) affinity proteins of non-immunoglobulin origin that have been generated to specifically interact with a large number of clinically important molecular targets. In this thesis, Affibody molecules have been employed as tracers for radionuclide molecular imaging of HER2- and IGF-1R-expressing tumors, paper I-IV, and for surface knock- down of EGFR, paper V. In paper I, a tag with the amino acid sequence HEHEHE was fused to the N-terminus of a HER2-specific Affibody molecule, (ZHER2), and was shown to enable facile IMAC purification and efficient tri-carbonyl 99mTc-labeling. In vivo evaluation of radioactivity uptake in different organs showed an improved biodistribution, including a 10-fold lower radioactivity uptake in liver, compared to the same construct with a H6-tag. In paper II, it was further shown that an N-terminally placed HEHEHE- tag on ZHER2 provided lower unspecific uptake of radioactivity in liver compared to its H6- tagged counterpart even when radiolabeling was at the C-terminus using alternative 99m 111 125 chemistries to attach Tc, In or I. In paper III, the H6-tag’s composition and position was varied with regards to charge, hydrophobicity and its C- or N-terminal placement on ZHER2. Among the ten variants investigated, it was found that an N-terminal HEHEHE-tag provided the most favorable overall biodistribution profile and that introduction of hydrophobic and positively charged amino acids provoked liver uptake of radioactivity. In paper IV, the HEHEHE-tag was shown to enable IMAC purification and tri-carbonyl 99mTc-labeling of an IGF-1R-specific Affibody molecule and improved its overall biodistribution when compared to the same construct with a H6-tag. In paper V, the aim was to develop an intracellular receptor-entrapment system to reduce the surface levels of EGFR. An EGFR-specific Affibody molecule was expressed as a fusion to different mutants of an intracellular transport protein in SKOV-3 cells, resulting in a collection of cell lines with 50%, 60%, 80% and 96% reduced surface level of EGFR. Analysis of the proliferation rate of these cell lines showed that a modest reduction (15%) in proliferation occurs between 60% and 80% reduction of the surface level of EGFR. Keywords: Affibody molecules, EGFR, HER2, IGF-1R, H6-tag, radionuclide molecular imaging, tracer, intracellular targeting. © Camilla Hofström 2013 V ______________________________________________________________________________ List of publications This thesis is based on the papers listed below, which will be referred to in the text by their Roman numerals (I-V). The papers are included in the Appendix. I. Tolmachev V, Hofström C, Malmberg J, Ahlgren S, Hosseinimehr S J, Sandström M, Abrahmsén L, Orlova A, Gräslund T. (2010). HEHEHE-tagged Affibody molecule may be purified by IMAC, is conveniently labeled with [99mTc(CO)3]+, and shows improved biodistribution with reduced hepatic radioactivity accumulation. Bioconjug. Chem. 21(11):2013-22. II. Hofström C, Orlova A, Altai M, Wangsell F, Gräslund T, Tolmachev V. (2011). Use of a HEHEHE purification tag instead of a hexahistidine tag improves biodistribution of Affibody molecules site-specifically labeled with 99mTc, 111In, and 125I. J Med Chem. 54(11):3817-26. III. Hofström C, Altai M, Honarvar H, Strand J, Malmberg J, Hosseinimehr S J, Orlova A, Gräslund T, Tolmachev V. (2012). HAHAHA, HEHEHE, HIHIHI or HKHKHK: influence of position and composition of histidine 99m + containing tags on biodistribution of [ Tc(CO)3] -labeled Affibody molecules. Manuscript. IV. Orlova A, Hofström C, Strand J, Varasteh Z, Sandstrom M, Andersson K, 99m + Tolmachev V, Gräslund T. (2012). [ Tc(CO)3] -(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor 1 receptor expression in malignant tumors. Eur J Nucl Med Mol Imaging. Epub ahead of print, PMID: 23179942. V. Hofström C, Stadler C, Vernet E, Gräslund T. (2012). Step-wise down- regulation of the epidermal growth factor receptor by affinity-based intracellular redirection. Manuscript. All papers are reproduced with permission from the copyright holders VI ______________________________________________________________________________ Other publications Larsson K, Hofström C, Lindskog C, Hansson M, Angelidou P, Hökfelt T, Uhlén M, Wernérus H, Gräslund T, Hober S. (2011). Novel antigen design for the generation of antibodies to G-protein-coupled receptors. J immunol. Methods. 70(1-2):14-23. Lindberg H*, Hofström C*, Altai M, Honorvar H, Wållberg H, Orlova A, Ståhl S, Gräslund T, Tolmachev V. (2012). Evaluation of a HER-targeting Affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for 99mTc-labelling at the C terminus. Tumor biol. 33(3):641-51. Tolmachev V, Malmberg J, Hofström C, Abrahmsén L, Bergman T, Sjöberg A, Sandström M, Gräslund T, Orlova A. (2012). Imaging of insulin-like growth factor type 1 receptor in prostate cancer xenografts using the Affibody molecule 111In- DOTA-ZIGF1R:4551. J Nucl Med. 53(1):90-7. * These authors contributed equally to this work VII ______________________________________________________________________________ Till minne av min far IX ______________________________________________________________________________ Contents Introduction ................................................................................................... 1 1. Affinity protein classes ................................................................................ 3 1.2 Antibodies ............................................................................................................. 4 1.3 Antibody derivatives .............................................................................................. 6 1.3 Alternative scaffolds ............................................................................................... 8 1.3.1 Affibody molecules .................................................................................... 9 1.3.2 DAPRins ................................................................................................. 10 1.3.3 Adnectins ................................................................................................ 11 1.3.4 Anticalins ................................................................................................ 12 1.3.5 Knottins .................................................................................................. 12 2. In vivo molecular imaging of cancer ......................................................... 13 2.1 Radiolabeling ...................................................................................................... 15 2.2 Biodistribution .................................................................................................... 18 3. Intracellular targeting ............................................................................... 20 3.1 Intrabody formats ................................................................................................ 20 3.2 Intrabody mode of action .................................................................................... 22 3.3 Intrabody for therapy .......................................................................................... 22 3. Intrabody expression and gene delivery ................................................................ 24 4. Present investigation ................................................................................. 26 4.1 Affibody molecules for radionuclide molecular imaging of HER2 and IGF-1R ... 27 4.1.2 A HEHEHE-tagged Affibody molecule may purified by IMAC, is 99m + conveniently labeled with [ Tc(CO)3] , and shows improved biodistribution with reduced hepatic radioactivity accumulation (paper I) ................................ 30 4.1.3 Use of a HEHEHE purification tag instead of a hexahistidine tag improves biodistribution of Affibody molecules site-specifically labeled with 99mTc, 111In, and 125I (paper II) ............................................................................... 33 4.1.4 HAHAHA, HEHEHE, HIHIHI or HKHKHK: influence of position and 99m + composition of histidine containing tags on biodistribution of [ Tc(CO)3] - labeled Affibody molecules (paper III) .............................................................. 36 99m + 4.1.5 [ Tc(CO)3] -(HE)3-ZIGF1R:4551
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