| 1. |
- Almqvist, Ylva, et al.
(författare)
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In vitro characterization of 211 At-labeled antibody A33 : a potential therapeutic agent against metastatic colorectal carcinoma
- 2005
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 20:5, s. 514-523
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Tidskriftsartikel (refereegranskat)abstract
- The humanized antibody A33 binds to the A33 antigen, expressed in 95% of primary and metastatic colorectal carcinomas. The restricted pattern of expression in normal tissue makes this antigen a possible target for radioimmunotherapy of colorectal micrometastases. In this study, the A33 antibody was labeled with the therapeutic nuclide 211At using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB). The in vitro characteristics of the 211At-benzoate-A33 conjugate (211At-A33) were investigated and found to be similar to those of 125I-benzoate-A33 (125I-A33) in different assays. Both conjugates bound with high affinity to SW1222 cells (Kd = 1.7 ± 0.2 nM, and 1.8 ± 0.1 nM for 211At-A33 and 125I-A33, respectively), and both showed good intracellular retention (70% of the radioactivity was still cell associated after 20 hours). The cytotoxic effect of 211At-A33 was also confirmed. After incubation with 211At-A33, SW1222 cells had a survival of approximately 0.3% when exposed to some 150 decays per cell (DPC). The cytotoxic effect was found to be dose-dependent, as cells exposed to only 56 DPC had a survival of approximately 5%. The 211At-A33 conjugate shows promise as a potential radioimmunotherapy agent for treatment of micrometastases originating from colorectal carcinoma.
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| 2. |
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| 3. |
- Rydengård, Victoria, et al.
(författare)
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Histidine-rich glycoprotein protects from systemic Candida infection
- 2008
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 4:8, s. e1000116-
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Tidskriftsartikel (refereegranskat)abstract
- Fungi, such as Candida spp., are commonly found on the skin and at mucosal surfaces. Yet, they rarely cause invasive infections in immunocompetent individuals, an observation reflecting the ability of our innate immune system to control potentially invasive microbes found at biological boundaries. Antimicrobial proteins and peptides are becoming increasingly recognized as important effectors of innate immunity. This is illustrated further by the present investigation, demonstrating a novel antifungal role of histidine-rich glycoprotein (HRG), an abundant and multimodular plasma protein. HRG bound to Candida cells, and induced breaks in the cell walls of the organisms. Correspondingly, HRG preferentially lysed ergosterol-containing liposomes but not cholesterol-containing ones, indicating a specificity for fungal versus other types of eukaryotic membranes. Both antifungal and membrane-rupturing activities of HRG were enhanced at low pH, and mapped to the histidine-rich region of the protein. Ex vivo, HRG-containing plasma as well as fibrin clots exerted antifungal effects. In vivo, Hrg(-/-) mice were susceptible to infection by C. albicans, in contrast to wild-type mice, which were highly resistant to infection. The results demonstrate a key and previously unknown antifungal role of HRG in innate immunity.
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| 4. |
- Blombäck, Anna, 1975-, et al.
(författare)
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Företaget som samhällsentreprenör
- 2009
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Ingår i: Samhällets Entreprenörer: En forskarantologi om samhällsentreprenörskap. - Stockholm : KK-stiftelsen. - 9789197691444
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Bokkapitel (refereegranskat)
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| 5. |
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| 6. |
- EL Andaloussi-Lilja, Johanna, et al.
(författare)
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TRPV1 expression and activity during retinoic acid-induced neuronal differentiation
- 2009
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Ingår i: Neurochemistry International. - : Elsevier BV. - 0197-0186 .- 1872-9754. ; 55:8, s. 768-774
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Tidskriftsartikel (refereegranskat)abstract
- The transient receptor potential vanilloid subtype 1 (TRPV1) is a Ca2+-permeable channel primarily expressed in dorsal root ganglion neurons. Besides its function in thermogenic nociception and neurogenic inflammation, TRPV1 is involved in cell migration, cytoskeleton reorganisation and in neuronal guidance. To explore the TRPV1 level and activity during conditions for neuronal maturation, TRPV1-expressing SHSY5Y neuroblastoma cells were differentiated into a neuronal phenotype using all-trans-retinoic acid (RA). We show that RA highly up-regulated the total and cell surface TRPV1 protein expression but the TRPV1 mRNA level was unaffected. The up-regulated receptors were localised to the cell bodies and the developed neurites. Furthermore, RA increased both the basal intracellular free Ca2+ concentration by 30 % as well as the relative capsaicin-induced Ca2+ influx. The results show that TRPV1 protein expression increases during RA-induced differentiation in vitro, which generates an altered intracellular Ca2+ homeostasis.
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| 7. |
- Gustavsson, Maria, 1962-, et al.
(författare)
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Lokalt ledarskap i en global organisation : kvinnors och mäns möjligheter att bli chefer och utöva ledarskap inom ett verkstadsindustriföretag
- 2008
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Frågor som rör chef- och ledarskap genererar alltid ett stort intresse såväl i arbetslivet som inom forskning. Det tema som fokuseras i den här rapporten är chef-/ledarskap och kön, särskilt könsfördelningen på ledande befattningar. I dagsläget är merparten av alla chefer i svenskt arbetsliv män. Män är överrepresenterade på chefsbefattningar i relation till samtliga anställda män i såväl privat som offentlig sektor. På de högsta chefsbefattningarna blir mansdominansen än tydligare (SCB, 2006). Mansdominansen på ledande befattningar kan sägas utgöra en utgångspunkt för de forskningsfrågor som formulerats inom forskningsområdet chef-/ledarskap och kön. Forskningsfrågorna handlar t.ex. om varför så få kvinnor är chefer samt på senare år om hur ledarskap är könsmärkt, dvs. hur ledarskap förknippas med kön. En återkommande fråga i mansdominerade organisationer är: Hur kan vi få fler kvinnor på ledande befattningar? Det är just denna problematik som fokuseras i föreliggande rapport som sammanfattar erfarenheter från ett forsknings- och utvecklingsprojekt som pågick från senhösten 2007 till senhösten 2008.Syftet med föreliggande rapport är att kartlägga och analysera villkor för kvinnor och män att bli chefer och att utöva chef- och ledarskap, samt varför få kvinnor har chefspositioner. Utgångspunkten för denna analys är en empirisk studie inom ett globalt verkstadsindustriföretag baserad på intervjuer med chefer, både kvinnor och män, på olika chefsnivåer och från olika divisioner. Följande mer specifika frågeställningar har formulerats:Vad karaktäriserar chefernas uppfattningar om ledarskap, chefsrekrytering, lärande och karriär, jämställdhet samt hälsa i företaget?Vilka förutsättningar finns för kvinnor och män att rekryteras till chefspositioner samt utöva chef- och ledarskap i företaget?Vilka orsaker finns till varför få kvinnor har chefspositioner i företaget?För att kunna diskutera skillnader mellan kvinnors och mäns uppfattningar och villkor närmar vi oss forskningsfrågorna utifrån ett genusperspektiv. Med genusperspektiv avser vi i denna rapport synsättet att vi formas till kvinnor och män genom det vi gör, och de aktiviteter vi deltar i, i samspel med andra människor i det dagliga arbetet. Våra könsidentiteter är beroende av rådande, socialt konstruerade, föreställningar i samhället och vi lär oss och lär oss att förhålla oss till dessa föreställningar i det dagliga arbetet. Vi utvecklar dessa tankar ytterligare i kapitel 2.
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| 8. |
- Höglund, Johanna, et al.
(författare)
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Cellular processing in the SW1222 cell line of mAb A33 directly and indirectly radiohalogenated
- 2006
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Ingår i: Oncology Reports. - 1021-335X .- 1791-2431. ; 16:1, s. 159-63
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Tidskriftsartikel (refereegranskat)abstract
- Investigations into the cellular processing of radiolabeled monoclonal antibodies (mAbs) for their further use in radioimmunodiagnosis and cancer therapy are needed in order to understand the fate of internalized and catabolized mAbs. The anti-colorectal cancer mAb, A33, was labelled with 76Br and 125I using the direct Chloramine-T method, or by labelling N-succinimidyl para-(tri-methylstannyl) benzoate and its further conjugation to the mAb. The cellular processing of the four conjugates was investigated in SW1222 cells in vitro. Uptake of mAb was rapid, peaking after 14-16 h. Intracellular degradation was slow and the early loss of radioactivity was due to dissociation of cell-surface bound mAb. The indirect labelling resulted in stronger binding of the mAb as well as prolonged intracellular retention of the radiolabel. Direct and indirect halogen radiolabelling results in different cell-processing patterns of radiolabels, and radioactive catabolic products follow different routes of cellular excretion. The results of this cellular study indicate that indirect labelling is preferable to the direct Chloramine-T method.
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| 9. |
- Jonsson, Anna, 1967-, et al.
(författare)
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Att engagera sig i vattenfrågor - varför, hur mycket och vem?
- 2006
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Ingår i: På tal om vatten. - Göteborg : VASTRA. - 9163189151 ; , s. 93-122
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- På tal om vatten är en bok om hållbar vattenförvaltning och strategisk planering av åtgärder inom avrinningsområden. Med denna bok, som har vuxit fram i samarbete mellan oss som arbetat inom Vattenstrategiska forskningsprogrammet, VASTRA, vill vi dela med oss av våra forskningserfarenheter så att de kan komma dem till del som jobbar med vattenfrågor i praktiken ute i Vattensverige.Transporter av växtnäringsämnen och övergödning av sjöar och hav är ett stort vattenproblem, som vi i Sverige trots omfattande åtgärder ännu inte fått bukt med. Vi vill med den här boken peka på möjliga vägar framåt för att även diffusa utsläpp skall kunna begränsas på ett mer systematiskt och effektivt sätt. Det gäller att få fram kunskap och användbara beslutsunderlag och att utforma realistiska former för samverkan och samarbete på lokal och regional nivå så att åtgärder kan utformas klokt och få intressenternas förståelse och stöd. Deras medverkan i den strategiska planeringen är en viktig förutsättning för att kunna genomföra kostnadseffektiva åtgärdsprogram, som accepteras av dem som bor och verkar inom ett avrinningsområde.Sommaren 2006 kan vi konstatera att resurserna och de organisatoriska förutsättningarna i vattenförvaltningen för att genomföra effektiva åtgärder fortfarande lämnar en hel del övrigt att önska. I den här boken pekar vi på några av de brister som bidrar till att göra det så svårt att komma åt diffusa utsläpp från olika områden och verksamheter. Den kunskap och de verktyg och metoder som vi inom VASTRA har utformat för beslutsstöd och deltagande kan förhoppningsvis vara till hjälp på vägen mot att komma till rätta med några av bristerna.Vår förhoppning är att På tal om vatten även skall ge inspiration till en fortsatt debatt kring de organisatoriska formerna för deltagande, inflytande och genomförande av åtgärder för bättre vattenkvalitet. För ytterst är det ju en självklarhet att vattnet är allas vår angelägenhet, både som möjlighet och ansvar.
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| 10. |
- Kullberg, Erika Bohl, et al.
(författare)
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An aminoacridine derivative for radionuclide therapy : DNA binding properties studied in a novel cell-free in vitro assay
- 2005
-
Ingår i: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 27:5, s. 1355-60
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Tidskriftsartikel (refereegranskat)abstract
- Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer therapy of disseminated disease. In this work, the aminoacridine compound N-[3-(acridine-9-ylamino)-propyl]-3-iodobenzamide (A3) labelled with the Auger-emitting nuclide 125I using Chloramine-T was studied. Optimal labelling conditions of 125I-A3 were investigated and the interaction with DNA was studied using a novel cell-free in vitro assay with naked human genomic DNA in agarose plugs. This novel assay showed to be simple and reliable. The results verify that 125I-A3 specifically binds DNA with low dissociation and is potent in causing double-strand breaks, yielding 1.0-1.4 breaks per decay. In conclusion, 125I-A3 is a most suitable DNA-binding compound for future therapeutic studies of Auger-electron emitters like 125I.
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| 11. |
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| 12. |
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| 13. |
- Lundqvist, Anna, 1944-, et al.
(författare)
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Driving after brain injury : Self-awareness and coping at the tactical level of control
- 2007
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Ingår i: Brain Injury. - : Taylor & Francis. - 0269-9052 .- 1362-301X. ; 21:11, s. 1109-1117
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study whether metacognition is a prerequisite for coping at the tactical level of driving. Research design: A consecutive series of 30 drivers with acquired brain injury were assessed concerning cognitive functions and driving performance. In addition the drivers assessed their driving performance through self-rating. Results: On average the drivers had cognitive impairments compared to a healthy reference group. The group that passed the driving test and the group that failed the driving test did not differ in terms of cognitive functions. Neither did they differ in their self-ratings of driving performance. However, the group that failed the driving test significantly over-estimated their performances as compared to the assessments made by the professional driving inspector, while the group that passed the test made more accurate self-ratings. Conclusions: One interpretation of these results is that the group that made a more realistic evaluation of their driving performance were more aware of their cognitive capacity compared to those who failed the driving test. They seemed to have a better ability to adjust their driving behaviour at a tactical level. Thus, the subject's metacognition, awareness of his/her own cognitive capacity, is important for coping with cognitive impairments at tactical driving.
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| 14. |
- Lundqvist, Anna, et al.
(författare)
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Factors influencing driving 10 years after brain injury
- 2008
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Ingår i: Brain Injury. - : Informa UK Limited. - 0269-9052 .- 1362-301X. ; 22:4, s. 295-304
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study long-term consequences of brain injury on health status, driving characteristics and car accidents. To study whether driving 10 years after brain injury was retrospectively related to cognitive functioning and on-road driving performance 10 years before. Research design: A semi-structured telephone interview with 38 patients with sequelae of brain injury and 49 healthy controls was used. Results: Hypertension, heart disease and vascular disorder were the most frequently reported diseases. The patients reported fatigue, irritability, memory and initiative problems. Concentration and vision problems influenced their driving. Patients had more car accidents reported to an insurance company during the observation period than control subjects. Present driving was retrospectively significantly related to neuropsychological test results but not to on-road test outcome 10 years before. Car accidents were not related to neuropsychological test results or to on-road test outcome 10 years back. Half of the dropouts were stroke patients and they performed significantly worse on the neuropsychological tests but not on the on-road test 10 years before. Conclusion: Neuropsychological tests focusing on information processing speed and attention is a useful screening tool for predicting driving competence. Stroke patients are vulnerable if they continue to drive and need to be evaluated for their driving capacity to drive.
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| 15. |
- Lundqvist, Fredrik, et al.
(författare)
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Removal of non-process elements from hardwood chips prior to kraft cooking
- 2006
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Ingår i: Appita journal. - 1038-6807. ; 59:6, s. 493-499
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Tidskriftsartikel (refereegranskat)abstract
- The major part of the intake of non-process elements (NPEs) to the pulp mill is via the wood chips. Some of the problems associated with NPEs are for example, precipitation of sparingly soluble calcium salts in the fibre line and in the recovery department. In order to investigate the possibilities of reducing the intake of NPEs via hardwood chips to the pulp mill, laboratory studies on the acidic leaching of birch and eucalypt chips were carried out. The results showed that potassium, magnesium and manganese were removed from both wood species at similar rates. The removal of calcium was however significantly slower from eucalypt than from birch. Removal of NPEs from birch wood chips prior to cooking resulted in a higher rate of delignification, a higher unbleached brightness and a higher viscosity. In the case of eucalypt, acidic leaching had no effect on the rate of delignification. The positive effect of acidic leaching of birch chips was found to be due to a lower content of calcium in the cooking stage.
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| 16. |
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| 17. |
- Lundqvist, Lennart J, 1939, et al.
(författare)
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Engagera sig i vattenfrågor – varför, hur och vem?
- 2006
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Ingår i: På tal om vatten. En kunskapsbok om steg på vägen mot en hållbar vattenförvaltning (red. B. Hägerhäll Aniansson. ; , s. 93-122
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 18. |
- Lundqvist, Pernilla, 1980, et al.
(författare)
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IFRS Implementation in Listed Companies – Identification of Factors Leading to Inconsistent Application
- 2008
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Ingår i: 31st Annual Congress EAA, April 23 - 25, Rotterdam, The Netherlands.
-
Konferensbidrag (refereegranskat)abstract
- This paper presents an exploratory study of factors that lead to inconsistent application of International Financial Reporting Standards (IFRS). We study the reasons for diversity in implementation of IFRS. The literature suggests a large number of different factors that help explain accounting choices, both deliberate and non-deliberate. We use accounting practice as a starting point. Through observation two cases are studied. First, the entire process of IFRS implementation is studied, from local GAAP to full IFRS. Second, we study purchase price allocation in business combinations accounted for according to IFRS 3. The method used is participant observation, where the researcher participated in the actual application of IFRS in selected listed companies. All observations were done in a Swedish setting. We relate our findings to those factors suggested in the existing literature. Consistent with the literature we find that bonus plans, national legal setting and existing practice are influential factors. Additional factors, not discussed much in the literature, are lack of resources and knowledge, and the development of local practice. We also find an interaction between existing practice and economic choice, suggesting that combining different parts of the accounting choice literature would be beneficial.
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| 19. |
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| 20. |
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| 21. |
- Mume, Eskender, et al.
(författare)
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Radiobromination of humanized anti-HER2 monoclonal antibody trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate, a potential label for immunoPET
- 2005
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 32:6, s. 613-22
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Tidskriftsartikel (refereegranskat)abstract
- Combining the specificity of radioimmunoscintigraphy and the high sensitivity of PET in an in vivo detection technique could improve the quality of nuclear diagnostics. Positron-emitting nuclide (76)Br (T(1/2)=16.2 h) might be a possible candidate for labeling monoclonal antibodies (mAbs) and their fragments, provided that the appropriate labeling chemistry has been established. For internalizing antibodies, such as the humanized anti-HER2 monoclonal antibody, trastuzumab, radiobromine label should be residualizing, i.e., ensuring that radiocatabolites are trapped intracellularly after the proteolytic degradation of antibody. This study evaluated the chemistry of indirect radiobromination of trastuzumab using N-succinimidyl 5-(tributylstannyl)-3-pyridinecarboxylate. Literature data indicated that the use of this method provided residualizing properties for iodine and astatine labels on some antibodies. An optimized "one-pot" procedure produced an overall labeling efficiency of 45.5+/-1.2% over 15 min. The bromine label was stable under physiological and denaturing conditions. The labeled trastuzumab retained its capacity to bind specifically to HER2-expressing SKOV-3 ovarian carcinoma cells in vitro (immunoreactivity more than 75%). However, in vitro cell test did not demonstrate that the radiobromination of trastuzumab using N-succinimidyl 5-bromo-3-pyridinecarboxylate improves cellular retention of radioactivity in comparison with the use of N-succinimidyl 4-bromobenzoate.
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| 22. |
- Museth, Anna Katrine, et al.
(författare)
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The ALS-Associated Mutation G93A in Human Copper-Zinc Superoxide Dismutase Selectively Destabilizes the Remote Metal Binding Region
- 2009
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Ingår i: BIOCHEMISTRY. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 48:37, s. 8817-8829
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Tidskriftsartikel (refereegranskat)abstract
- More than 100 distinct mutations in the gene (SOD 1) for human copper-zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS). Studies of these mutant proteins, which often have been performed under far from physiological conditions, have indicated effects oil protein stabilities, catalytic activity, kind metal binding affinities but with no common pattern. Also, with the knowledge that ALS is a late onset disease it is apparent that protein interactions which contribute to the disorder might, in the natural cellular milieu, depend on a delicate balance between intrinsic protein properties. In this study, we have used experimental conditions as near as possible to the in vivo conditions to reduce artifacts emanating from the experimental setup. Using H-1-N-15 HSQC NMR spectroscopy, we have analyzed hydrogen exchange at the amide groups of wild-type (wt) CuZnSOD and the fALS-associated G93A SOD variant in their fully metalated states. From analyses of the exchange pattern, we have characterized the local dynamics at 64% of all positions in detail in both the wt and G93A protein. The results show that the G93A mutation had no effect on the dynamics at a majority of the investigated positions. However, the mutation results in local destabilization at the site of the Mutation and also in stabilization at a few positions that were apparently scattered over the entire protein surface. Most remarkably, the mutation selectively destabilized the remote metal binding region. The results indicate that the metal binding region may affect the intermolecular protein-protein interactions which cause formation of protein aggregates.
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| 23. |
- Orlova, Anna, et al.
(författare)
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Evaluation of [(111/114m)In]CHX-A''-DTPA-ZHER2:342, an affibody ligand coniugate for targeting of HER2-expressing malignant tumors
- 2007
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Ingår i: The Quarterly Journal of Nuclear Medicine and Molecular Imaging. - 1824-4785. ; 51:4, s. 314-323
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Radionuclide imaging of the HER2 receptor, which is a target for trastuzumab therapy, can provide important diagnostic information. Further, targeting radionuclide therapy might be an option for treatment of HER2 expressing tumors. The phage-display selected Affibody ligand Z(HER2:342), which binds to HER2 with an affinity of 22 pM, may here play an important role. The small size of the Z(HER2:342), 7.5 kDa, enables quick tumor localization and fast blood clearance. Earlier, successful targeting of HER2-expressing xenografts using Z(HER2:342) labeled using [(111)In]benzyl-DTPA was reported. By changing to the CHX-A''-DTPA chelator, the stability and labeling kinetics of the radiometal-Z(HER2:342) conjugate can be improved. The aim of this study was to evaluate the labeling of the CHX-A''-DTPA-Z(HER2:342) conjugate with (111)In for diagnostic imaging and with (114m)In for locoregional radionuclide therapy. METHODS: The isothiocyanate derivative of CHX-A''-DTPA was coupled to Z(HER2:342) in alkaline conditions at 37 degrees C. The conjugate was labeled with both (111)In and (114m)In and evaluated in vitro and in vivo. RESULTS: Labeling with (111)In and (114m)In provided >95% yield after 30 min at RT. Specific radioactivity was 0.5 and 12 MBq/nmol, for (114m)In and (111)In, respectively. The radiolabeled conjugates demonstrated specific binding to HER2 expressing SKOV-3 cells. In mice bearing SKOV-3 xenografts, the tumor uptake of [(111)In]CHX-A''-DTPA-Z(HER2:342) 4 h postinjection was 10.3+/-3.6% IA/g and tumor-to-blood ratio about 190. CONCLUSION: [(111)In]CHX-A''-DTPA-Z(HER2:342) is a promising candidate for the visualization of HER2 expression in malignant tumors. Labeled with (114m)In it could also be used for locoregional treatment of HER2 expressing tumors.
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| 24. |
- Orlova, Anna, et al.
(författare)
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Radio-iodination of monoclonal antibody using potassium [125I]-(4-isothiocyanatobenzylammonio)-iodo-decahydro-closo-dodecaborate (iodo-DABI)
- 2006
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Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 26:2A, s. 1217-23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Negatively-charged polyhedral boron clusters can be easily halogenated with highly stable boron-halogen bonds and are promising in radionuclide diagnostics and cancer therapy. MATERIALS AND METHODS: The radio-iodination conditions for the closo-dodecaborate anion and for the conjugation of its labeled isothiocyanatobenzylammonio derivative to the monoclonal antibody (mAb) were optimized. RESULTS: The labeling yield was about 90% and the overall conjugation yield was 55-60%. The in vitro stability of the radio-iodinated mAb was good under physiological and non-physiological conditions. The immunoreactivity of the labeled mAb (SK-BR-3 cells) was retained in the one-pot two-step labeling. CONCLUSION: Negatively-charged polyhedral boron clusters can be used for indirect radio-iodination of mAbs.
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| 25. |
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| 26. |
- Tolmachev, Vladimir, et al.
(författare)
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Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific Affibody molecule
- 2007
-
Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 67:6, s. 2773-2782
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Tidskriftsartikel (refereegranskat)abstract
- A radiolabeled anti-HER2 Affibody molecule (Z(HER2:342)) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (approximately 7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (Z(HER2:342))(2) was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A''-DTPA and labeled with the low-energy beta-emitter (177)Lu. The obtained conjugate [CHX-A''-DTPA-ABD-(Z(HER2:342))(2)] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z(HER2:342))(2). Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non-HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) as a candidate for treatment of disseminated tumors with a high level of HER2 expression.
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| 27. |
- Tolmachev, Vladimir, et al.
(författare)
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The influence of Bz-DOTA and CHX-AaEuro(3)-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules : implications for In-114m-mediated targeting therapy
- 2009
-
Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 36:9, s. 1460-1468
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules represent a novel class of high-affinity agents for radionuclide tumour targeting. Fusion of the Affibody molecules with an albumin-binding domain (ABD) enables modification of the blood kinetics of the Affibody molecules and reduction of the renal dose. Lu-177-CHX-AaEuro(3)-DTPA-ABD-(Z(HER2:342))(2), an anti-HER2 Affibody molecule-ABD fusion protein has earlier demonstrated promising results in treatment of HER2-expressing micro-xenografts in mice. The use of the in vivo generator In-114m/In-114 as a label for ABD-fused Affibody molecules would create preconditions for efficient treatment of both micrometastases (due to conversion and Auger electrons of In-114m) and bulky tumours (due to high-energy beta particles from the daughter nuclide In-114). The goal of this study was to investigate if different chelators influence the biodistribution of ABD-(Z(HER2:342))(2) and to find an optimal chelator for attachment of In-114m to the Affibody molecule-ABD fusion protein. Isothiocyanate derivatives of Bz-DOTA and CHX-AaEuro(3)-DTPA were coupled to ABD-(Z(HER2:342))(2). The cellular processing of both conjugates was studied in vitro. The influence of chelators on the biodistribution was investigated in mice using double isotope (In-114m and In-111) labelling. The apparent affinity of CHX-AaEuro(3)-DTPA-ABD-(Z(HER2:342))(2) and Bz-DOTA-ABD-(Z(HER2:342))(2) to the extracellular domain of HER2 was similar, 13.5 and 15.0 pM, respectively. It was found that both conjugates were internalized by SKOV-3 cells. The use of CHX-AaEuro(3)-DTPA provided better cellular retention of the radioactivity, better tumour accumulation of radioactivity and better tumour to organ dose ratios than Bz-DOTA-ABD-(Z(HER2:342))(2). CHX-AaEuro(3)-DTPA is more suitable for In-114m labelling of Affibody molecule-ABD fusion proteins for radionuclide therapy.
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