Radionuclide Therapy of HER2-Expressing Xenografts Using [177Lu]Lu-ABY-027 Affibody Molecule Alone and in Combination with Trastuzumab

Yongsheng Liu; Tianqi Xu; Anzhelika Vorobyeva; Annika Loftenius; Vitalina Bodenko; Anna Orlova; Fredrik Y Frejd; Vladimir Tolmachev

doi:10.3390/cancers15092409

Radionuclide Therapy of HER2-Expressing Xenografts Using [¹⁷⁷Lu]Lu-ABY-027 Affibody Molecule Alone and in Combination with Trastuzumab

Cancers (Basel). 2023 Apr 22;15(9):2409. doi: 10.3390/cancers15092409.

Authors

Yongsheng Liu¹, Tianqi Xu¹, Anzhelika Vorobyeva¹, Annika Loftenius², Vitalina Bodenko³, Anna Orlova⁴, Fredrik Y Frejd^{1

2}, Vladimir Tolmachev^{1

3}

Affiliations

¹ Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
² Affibody AB, 171 65 Solna, Sweden.
³ Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.
⁴ Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.

Abstract

ABY-027 is a scaffold-protein-based cancer-targeting agent. ABY-027 includes the second-generation Affibody molecule Z_HER2:2891, which binds to human epidermal growth factor receptor type 2 (HER2). An engineered albumin-binding domain is fused to Z_HER2:2891 to reduce renal uptake and increase bioavailability. The agent can be site-specifically labeled with a beta-emitting radionuclide ¹⁷⁷Lu using a DOTA chelator. The goals of this study were to test the hypotheses that a targeted radionuclide therapy using [¹⁷⁷Lu]Lu-ABY-027 could extend the survival of mice with HER2-expressing human xenografts and that co-treatment with [¹⁷⁷Lu]Lu-ABY-027 and the HER2-targeting antibody trastuzumab could enhance this effect. Balb/C nu/nu mice bearing HER2-expressing SKOV-3 xenografts were used as in vivo models. A pre-injection of trastuzumab did not reduce the uptake of [¹⁷⁷Lu]Lu-ABY-027 in tumors. Mice were treated with [¹⁷⁷Lu]Lu-ABY-027 or trastuzumab as monotherapies and a combination of these therapies. Mice treated with vehicle or unlabeled ABY-027 were used as controls. Targeted monotherapy using [¹⁷⁷Lu]Lu-ABY-027 improved the survival of mice and was more efficient than trastuzumab monotherapy. A combination of therapies utilizing [¹⁷⁷Lu]Lu-ABY-027 and trastuzumab improved the treatment outcome in comparison with monotherapies using these agents. In conclusion, [¹⁷⁷Lu]Lu-ABY-027 alone or in combination with trastuzumab could be a new potential agent for the treatment of HER2-expressing tumors.

Keywords: Affibody molecule; HER2; lutetium-177; radionuclide therapy.

Abstract

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