A Comparison of in vivo Half-life Extension of Affibody-Drug Conjugates by PASylation, XTENylation and Albumin Binding

QC 20230824
Drug conjugates based on engineered scaffold affinity proteins hold promise to become potent targeted cancer drugs in the future, and an important aspect is to provide them with optimal pharmacokinetic properties. In this study, we investigated different half-life extension technologies for HER2-specific affibody-drug conjugates (AffiDCs), and the effect they imposed on the uptake in tumors and normal organs and tissues. Two sizes of unstructured PAS and XTEN polypeptides (PAS300, PAS600, XTEN288, and XTEN576) and an albumin binding domain (ABD) were used for the comparison. The results showed that extension with the PAS or XTEN polypeptides as well as the addition of the ABD did not affect HER2 binding or the cytotoxic potential negatively. There was a difference in half-lives in mice, which ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including the PAS600 polypeptide. The highest absolute tumor uptake was found for the construct including the ABD, even though it did not have the longest in vivo half-life (9.0 h). Consequently, the construct with the ABD gave the highest tumor-to-normal-organ ratios. In conclusion, PASylation, XTENylation, and the addition of an ABD appear to be viable strategies for half-life extension of affibody drug conjugates, with the best in vivo performance observed for the construct including the ABD.

TEKNIK OCH TEKNOLOGIER Industriell bioteknik Läkemedelsbioteknik hsv//swe
ENGINEERING AND TECHNOLOGY Industrial Biotechnology Pharmaceutical Biotechnology hsv//eng
Affibody molecule
HER2
PASylation
XTENylation
DM1
affibody-drug conjugate
half-life
biodistribution
Biotechnology
Bioteknologi

Av författaren/redakt...: Zhang, Jie; Bodenko, Vitalin ...; Larkina, Maria; Bezverkhnyaya, Y ...; Xu, Tianqi; Liao, Yunqi; visa fler...; Abouzayed, Ayman; Plotnikov, Evgen ...; Maria, Tretyakov ...; Yuldasheva, Feru ...; Belousov, Mikhai ...; Orlova, Anna; Tolmachev, Vladi ...; Gräslund, Torbjö ...; Vorobyeva, Anzhe ...; visa färre...

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TEKNIK OCH TEKNOLOGIER: TEKNIK OCH TEKNO ...; och Industriell biot ...; och Läkemedelsbiotek ...

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