uu.seUppsala universitets publikasjoner
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody-DM1 Drug Conjugates
KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.ORCID-id: 0000-0002-4778-3909
Vise andre og tillknytning
2019 (engelsk)Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 8, artikkel-id 1168Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
MDPI, 2019. Vol. 11, nr 8, artikkel-id 1168
Emneord [en]
affibody, drug conjugates, hepatic uptake, DM1
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-394647DOI: 10.3390/cancers11081168ISI: 000484438000128PubMedID: 31416167OAI: oai:DiVA.org:uu-394647DiVA, id: diva2:1361986
Forskningsfinansiär
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Cancer Society, CAN 2018/824Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Vinnova, 2016-04060Vinnova, 2019-00104Swedish Society for Medical Research (SSMF)Tilgjengelig fra: 2019-10-17 Laget: 2019-10-17 Sist oppdatert: 2019-10-17bibliografisk kontrollert

Open Access i DiVA

fulltekst(10348 kB)18 nedlastinger
Filinformasjon
Fil FULLTEXT01.pdfFilstørrelse 10348 kBChecksum SHA-512
61c95c687e2bb3a6cf4cb1c8f5103783881b52a925a86fe2739223d6c320ea5932232ee3f38ee0aedff32d02245062d072dcf7237d7404ea70646ccd9596f2b6
Type fulltextMimetype application/pdf

Andre lenker

Forlagets fulltekstPubMed

Personposter BETA

Altai, MohamedRinne, Sara S.Vorobyeva, AnzhelikaTolmachev, VladimirOrlova, Anna

Søk i DiVA

Av forfatter/redaktør
Altai, MohamedRinne, Sara S.Vorobyeva, AnzhelikaTolmachev, VladimirOrlova, Anna
Av organisasjonen
I samme tidsskrift
Cancers

Søk utenfor DiVA

GoogleGoogle Scholar
Totalt: 18 nedlastinger
Antall nedlastinger er summen av alle nedlastinger av alle fulltekster. Det kan for eksempel være tidligere versjoner som er ikke lenger tilgjengelige

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 25 treff
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf