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Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody ® Molecules 177 Lu-ABY-271 and 177 Lu-ABY-027: Impact of DOTA Position on ABD Domain.
- Source :
- Pharmaceutics; Jun2021, Vol. 13 Issue 6, p839, 1p
- Publication Year :
- 2021
-
Abstract
- Radiolabeled Affibody-based targeting agent <superscript>177</superscript>Lu-ABY-027, a fusion of an anti-HER2 Affibody molecule with albumin binding domain (ABD) site-specifically labeled at the C-terminus, has demonstrated a promising biodistribution profile in mice; binding of the construct to albumin prevents glomerular filtration and significantly reduces renal uptake. In this study, we tested the hypothesis that site-specific positioning of the chelator at helix 1 of ABD, at a maximum distance from the albumin binding site, would further increase the strength of binding to albumin and decrease the renal uptake. The new construct, ABY-271 with DOTA conjugated at the back of ABD, has been labelled with <superscript>177</superscript>Lu. Targeting properties of <superscript>177</superscript>Lu-ABY-271 and <superscript>177</superscript>Lu-ABY-027 were compared directly. <superscript>177</superscript>Lu-ABY-271 specifically accumulated in SKOV-3 xenografts in mice. The tumor uptake of <superscript>177</superscript>Lu-ABY-271 exceeded uptake in any other organ 24 h and later after injection. However, the renal uptake of <superscript>177</superscript>Lu-ABY-271 was two-fold higher than the uptake of <superscript>177</superscript>Lu-ABY-027. Thus, the placement of chelator on helix 1 of ABD does not provide desirable reduction of renal uptake. To conclude, minimal modification of the design of Affibody molecules has a strong effect on biodistribution, which cannot be predicted a priori. This necessitates extensive structure-properties relationship studies to find an optimal design of Affibody-based targeting agents for therapy. [ABSTRACT FROM AUTHOR]
- Subjects :
- MOLECULES
MINIMAL design
SCAFFOLD proteins
INJECTIONS
BINDING sites
ALBUMINS
Subjects
Details
- Language :
- English
- ISSN :
- 19994923
- Volume :
- 13
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 151060193
- Full Text :
- https://doi.org/10.3390/pharmaceutics13060839