Sökning: onr:"swepub:oai:DiVA.org:kth-261042" > Incorporation of a ...
Fältnamn | Indikatorer | Metadata |
---|---|---|
000 | 04839naa a2200517 4500 | |
001 | oai:DiVA.org:kth-261042 | |
003 | SwePub | |
008 | 191002s2019 | |||||||||||000 ||eng| | |
009 | oai:DiVA.org:uu-394647 | |
024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-2610422 URI |
024 | 7 | a https://doi.org/10.3390/cancers110811682 DOI |
024 | 7 | a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3946472 URI |
040 | a (SwePub)kthd (SwePub)uu | |
041 | a engb eng | |
042 | 9 SwePub | |
072 | 7 | a ref2 swepub-contenttype |
072 | 7 | a art2 swepub-publicationtype |
100 | 1 | a Ding, Haozhongu KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden4 aut0 (Swepub:kth)u18o3ynm |
245 | 1 0 | a Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates |
264 | c 2019-08-14 | |
264 | 1 | b MDPI,c 2019 |
338 | a print2 rdacarrier | |
500 | a QC 20191002 | |
520 | a Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previous clinical experience with antibody drug conjugates have revealed a moderateto high-grade hepatotoxicity in treated patients, which merits efforts to also minimize hepatic uptake of the AffiDCs. In this study, the aim was to reduce the hepatic uptake of AffiDCs and optimize their in vivo targeting properties. We have investigated if incorporation of hydrophilic glutamate-based spacers adjacent to MC-DM1 in the AffiDC, (Z(HER2:2891))(2) -ABD-MC-DM1, would counteract the hydrophobic nature of MC-DM1 and, hence, reduce hepatic uptake. Two new AffiDCs including either a triglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-3-MC-DM1, or a hexaglutamate-spacer-, (Z(HER2:2891))(2)-ABD-E-6-MC-DM1 next to the site of MC-DM1 conjugation were designed. We radiolabeled the hydrophilized AffiDCs and compared them, both in vitro and in vivo, with the previously investigated (Z(HER2:2891))(2)-ABD-MC-DM1 drug conjugate containing no glutamate spacer. All three AffiDCs demonstrated specific binding to HER2 and comparable in vitro cytotoxicity. A comparative biodistribution study of the three radiolabeled AffiDCs showed that the addition of glutamates reduced drug accumulation in the liver while preserving the tumor uptake. These results confirmed the relation between DM1 hydrophobicity and liver accumulation. We believe that the drug development approach described here may also be useful for other affinity protein-based drug conjugates to further improve their in vivo properties and facilitate their clinical translatability. | |
650 | 7 | a TEKNIK OCH TEKNOLOGIERx Industriell bioteknikx Medicinsk bioteknik0 (SwePub)209082 hsv//swe |
650 | 7 | a ENGINEERING AND TECHNOLOGYx Industrial Biotechnologyx Medical Biotechnology0 (SwePub)209082 hsv//eng |
650 | 7 | a NATURVETENSKAPx Biologix Biokemi och molekylärbiologi0 (SwePub)106022 hsv//swe |
650 | 7 | a NATURAL SCIENCESx Biological Sciencesx Biochemistry and Molecular Biology0 (SwePub)106022 hsv//eng |
653 | a affibody | |
653 | a drug conjugates | |
653 | a hepatic uptake | |
653 | a DM1 | |
700 | 1 | a Altai, Mohamedu Uppsala universitet,Medicinsk strålningsvetenskap4 aut0 (Swepub:uu)mohal988 |
700 | 1 | a Rinne, Sara S.u Uppsala universitet,Theranostics4 aut0 (Swepub:uu)sarri895 |
700 | 1 | a Vorobyeva, Anzhelikau Uppsala universitet,Medicinsk strålningsvetenskap4 aut0 (Swepub:uu)anzvo555 |
700 | 1 | a Tolmachev, Vladimiru Uppsala universitet,Medicinsk strålningsvetenskap4 aut0 (Swepub:uu)vladtolm |
700 | 1 | a Gräslund, Torbjörnu KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden4 aut0 (Swepub:kth)u1dl39rj |
700 | 1 | a Orlova, Anna,d 1960-u Uppsala universitet,Science for Life Laboratory, SciLifeLab,Theranostics4 aut0 (Swepub:uu)annaorlo |
710 | 2 | a KTHb Proteinvetenskap4 org |
773 | 0 | t Cancersd : MDPIg 11:8q 11:8x 2072-6694 |
856 | 4 | u https://www.mdpi.com/2072-6694/11/8/1168/pdf |
856 | 4 | u https://doi.org/10.3390/cancers11081168y Fulltext |
856 | 4 | u https://uu.diva-portal.org/smash/get/diva2:1361986/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print |
856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-261042 |
856 | 4 8 | u https://doi.org/10.3390/cancers11081168 |
856 | 4 8 | u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-394647 |
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