Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates

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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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Av författaren/redakt...: Ding, Haozhong; Altai, Mohamed; Rinne, Sara S.; Vorobyeva, Anzhe ...; Tolmachev, Vladi ...; Gräslund, Torbjö ...; visa fler...; Orlova, Anna, 19 ...; visa färre...

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