Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD Domain
Radiolabeled Affibody-based targeting agent <sup>177</sup>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 albumi...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/6/839 |
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| author | Yongsheng Liu Anzhelika Vorobyeva Tianqi Xu Anna Orlova Annika Loftenius Theresa Bengtsson Per Jonasson Vladimir Tolmachev Fredrik Y. Frejd |
| author_facet | Yongsheng Liu Anzhelika Vorobyeva Tianqi Xu Anna Orlova Annika Loftenius Theresa Bengtsson Per Jonasson Vladimir Tolmachev Fredrik Y. Frejd |
| author_sort | Yongsheng Liu |
| collection | DOAJ |
| description | Radiolabeled Affibody-based targeting agent <sup>177</sup>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 <sup>177</sup>Lu. Targeting properties of <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027 were compared directly. <sup>177</sup>Lu-ABY-271 specifically accumulated in SKOV-3 xenografts in mice. The tumor uptake of <sup>177</sup>Lu-ABY-271 exceeded uptake in any other organ 24 h and later after injection. However, the renal uptake of <sup>177</sup>Lu-ABY-271 was two-fold higher than the uptake of <sup>177</sup>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. |
| first_indexed | 2024-03-10T10:38:38Z |
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| id | doaj.art-00f911f282414140bdb24d31c317d2e0 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T10:38:38Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj.art-00f911f282414140bdb24d31c317d2e02023-11-21T23:03:49ZengMDPI AGPharmaceutics1999-49232021-06-0113683910.3390/pharmaceutics13060839Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD DomainYongsheng Liu0Anzhelika Vorobyeva1Tianqi Xu2Anna Orlova3Annika Loftenius4Theresa Bengtsson5Per Jonasson6Vladimir Tolmachev7Fredrik Y. Frejd8Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenResearch Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, RussiaAffibody AB, 171 65 Solna, SwedenAffibody AB, 171 65 Solna, SwedenAffibody AB, 171 65 Solna, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenRadiolabeled Affibody-based targeting agent <sup>177</sup>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 <sup>177</sup>Lu. Targeting properties of <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027 were compared directly. <sup>177</sup>Lu-ABY-271 specifically accumulated in SKOV-3 xenografts in mice. The tumor uptake of <sup>177</sup>Lu-ABY-271 exceeded uptake in any other organ 24 h and later after injection. However, the renal uptake of <sup>177</sup>Lu-ABY-271 was two-fold higher than the uptake of <sup>177</sup>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.https://www.mdpi.com/1999-4923/13/6/839affibody moleculealbumin binding domain (ABD)<sup>177</sup>Luscaffold proteinradionuclide therapySKOV-3 xenograft |
| spellingShingle | Yongsheng Liu Anzhelika Vorobyeva Tianqi Xu Anna Orlova Annika Loftenius Theresa Bengtsson Per Jonasson Vladimir Tolmachev Fredrik Y. Frejd Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD Domain Pharmaceutics affibody molecule albumin binding domain (ABD) <sup>177</sup>Lu scaffold protein radionuclide therapy SKOV-3 xenograft |
| title | Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD Domain |
| title_full | Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD Domain |
| title_fullStr | Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD Domain |
| title_full_unstemmed | Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD Domain |
| title_short | Comparative Preclinical Evaluation of HER2-Targeting ABD-Fused Affibody<sup>®</sup> Molecules <sup>177</sup>Lu-ABY-271 and <sup>177</sup>Lu-ABY-027: Impact of DOTA Position on ABD Domain |
| title_sort | comparative preclinical evaluation of her2 targeting abd fused affibody sup r sup molecules sup 177 sup lu aby 271 and sup 177 sup lu aby 027 impact of dota position on abd domain |
| topic | affibody molecule albumin binding domain (ABD) <sup>177</sup>Lu scaffold protein radionuclide therapy SKOV-3 xenograft |
| url | https://www.mdpi.com/1999-4923/13/6/839 |
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